{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:19:32Z","timestamp":1787566772502,"version":"build-2736575974"},"reference-count":179,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["1ZIADK032103"],"award-info":[{"award-number":["1ZIADK032103"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1ZIADK032103"],"award-info":[{"award-number":["1ZIADK032103"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006084","name":"Office of AIDS Research","doi-asserted-by":"publisher","award":["1ZIADK075187"],"award-info":[{"award-number":["1ZIADK075187"]}],"id":[{"id":"10.13039\/100006084","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1ZIADK075187"],"award-info":[{"award-number":["1ZIADK075187"]}],"id":[{"id":"https:\/\/ror.org\/054j5yq82","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus\u2019s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility.<\/jats:p>","DOI":"10.3390\/biom16091221","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:03:41Z","timestamp":1787558621000},"page":"1221","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering Protein-Based HIV Entry Inhibitors: Advances, Challenges, and Translational Strategies"],"prefix":"10.3390","volume":"16","author":[{"given":"Rashmi","family":"Kumariya","sequence":"first","affiliation":[{"name":"Natural Products Chemistry Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carole A.","family":"Bewley","sequence":"additional","affiliation":[{"name":"Natural Products Chemistry Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","unstructured":"(2026, June 13). Global Statistics 2026, Available online: https:\/\/www.hiv.gov\/hiv-basics\/overview\/data-and-trends\/global-statistics."},{"key":"ref_2","unstructured":"(2026, June 13). AIDS 2026 Overview 2026. Available online: https:\/\/www.iasociety.org\/conferences\/aids2026\/about\/overview."},{"key":"ref_3","unstructured":"(2026, June 07). FDA-Approved HIV Medicines 2026, Available online: https:\/\/hivinfo.nih.gov\/understanding-hiv\/fact-sheets\/fda-approved-hiv-medicines."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"a006866","DOI":"10.1101\/cshperspect.a006866","article-title":"HIV: Cell binding and entry","volume":"2","author":"Wilen","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.chembiol.2022.03.009","article-title":"Small-molecule HIV-1 entry inhibitors targeting the epitopes of broadly neutralizing antibodies","volume":"29","author":"Jiang","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Helmy, N.M., and Parang, K. (2024). The Role of Peptides in Combatting HIV Infection: Applications and Insights. Molecules, 29.","DOI":"10.20944\/preprints202409.0137.v1"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pu, J., Wang, Q., Xu, W., Lu, L., and Jiang, S. (2019). Development of protein- and peptide-based HIV entry inhibitors targeting gp120 or gp41. Viruses, 11.","DOI":"10.3390\/v11080705"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1021\/acs.bioconjchem.3c00314","article-title":"Peptide bispecifics inhibiting HIV-1 infection by an orthogonal chemical and supramolecular strategy","volume":"34","author":"Schauenburg","year":"2023","journal-title":"Bioconjug Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5793","DOI":"10.1021\/jacs.5c22670","article-title":"Nanobody-based bioconjugates as potent and broadly active inhibitors of HIV entry","volume":"148","author":"Saha","year":"2026","journal-title":"J. Am. Chem. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bi, W., Xu, W., Cheng, L., Xue, J., Wang, Q., Yu, F., Xia, S., Wang, Q., Li, G., and Qin, C. (2019). IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1008082"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Thavarajah, J.J., Honge, B.L., and Wejse, C.M. (2024). The use of broadly neutralizing antibodies (bNAbs) in HIV-1 treatment and prevention. Viruses, 16.","DOI":"10.20944\/preprints202405.0383.v1"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s11904-025-00744-1","article-title":"Future of bNAbs in HIV treatment","volume":"22","author":"Tebas","year":"2025","journal-title":"Curr. HIV\/AIDS Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/1742-4690-4-52","article-title":"Host factors influencing susceptibility to HIV infection and AIDS progression","volume":"4","author":"Lama","year":"2007","journal-title":"Retrovirology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14188","DOI":"10.1038\/s41598-023-41525-3","article-title":"Design of an alternate antibody fragment format that can be produced in the cytoplasm of Escherichia coli","volume":"13","author":"Tungekar","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1186\/s12951-024-02900-y","article-title":"Discovery of nanobodies: A comprehensive review of their applications and potential over the past five years","volume":"22","author":"Alexander","year":"2024","journal-title":"J. Nanobiotechnol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"648","DOI":"10.3390\/molecules20010648","article-title":"Lectins with anti-HIV activity: A review","volume":"20","author":"Akkouh","year":"2015","journal-title":"Molecules"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1139\/bcb-2016-0039","article-title":"Role of CXC chemokine receptor type 4 as a lactoferrin receptor","volume":"95","author":"Takayama","year":"2017","journal-title":"Biochem. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"572114","DOI":"10.3389\/fimmu.2020.572114","article-title":"Role of complement receptors (CRs) on DCs in anti-HIV-1 immunity","volume":"11","author":"Posch","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"764","DOI":"10.3389\/fimmu.2020.00764","article-title":"Defensins: A double-edged sword in host immunity","volume":"11","author":"Xu","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4201","DOI":"10.1128\/JVI.03608-14","article-title":"HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies","volume":"89","author":"Lynch","year":"2015","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Haim, H., Si, Z., Madani, N., Wang, L., Courter, J.R., Princiotto, A., Kassa, A., DeGrace, M., McGee-Estrada, K., and Mefford, M. (2009). Soluble CD4 and CD4-mimetic compounds inhibit HIV-1 infection by induction of a short-lived activated state. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000360"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1126\/science.3500514","article-title":"Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen","volume":"238","author":"Smith","year":"1987","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1128\/JVI.72.3.1876-1885.1998","article-title":"Neutralization sensitivity of human immunodeficiency virus type 1 primary isolates to antibodies and CD4-based reagents is independent of coreceptor usage","volume":"72","author":"Trkola","year":"1998","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9395","DOI":"10.1128\/JVI.05119-11","article-title":"Engineered single human CD4 domains as potent HIV-1 inhibitors and components of vaccine immunogens","volume":"85","author":"Chen","year":"2011","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1128\/JVI.02566-13","article-title":"Exceptionally potent and broadly cross-reactive, bispecific multivalent HIV-1 inhibitors based on single human CD4 and antibody domains","volume":"88","author":"Chen","year":"2014","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.omtn.2017.04.017","article-title":"Further characterization of the bifunctional HIV entry inhibitor sCD4-FI(T45)","volume":"7","author":"Falkenhagen","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.virol.2010.09.029","article-title":"The effect of sCD4 on the binding and accessibility of HIV-1 gp41 MPER epitopes to human monoclonal antibodies","volume":"408","author":"Peachman","year":"2010","journal-title":"Virology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e0115423","DOI":"10.1128\/jvi.01154-23","article-title":"Soluble CD4 and low molecular weight CD4-mimetic compounds sensitize cells to be killed by anti-HIV cytotoxic immunoconjugates","volume":"97","author":"Pincus","year":"2023","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nature14264","article-title":"AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges","volume":"519","author":"Gardner","year":"2015","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/viro.1997.8547","article-title":"A human IgG1 (b12) specific for the CD4 binding site of HIV-1 neutralizes by inhibiting the virus fusion entry process, but b12 Fab neutralizes by inhibiting a postfusion event","volume":"233","author":"McInerney","year":"1997","journal-title":"Virology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6961","DOI":"10.1038\/s41467-024-51414-6","article-title":"Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration","volume":"15","author":"Zhu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"893648","DOI":"10.3389\/fimmu.2022.893648","article-title":"Anti-HIV-1 nanobody-IgG1 constructs with improved neutralization potency and the ability to mediate fc effector functions","volume":"13","author":"Schriek","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"McCoy, L.E., Rutten, L., Frampton, D., Anderson, I., Granger, L., Bashford-Rogers, R., Dekkers, G., Strokappe, N.M., Seaman, M.S., and Koh, W. (2014). Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004552"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12069","DOI":"10.1128\/JVI.01379-08","article-title":"Llama antibody fragments with cross-subtype human immunodeficiency virus type 1 (HIV-1)-neutralizing properties and high affinity for HIV-1 gp120","volume":"82","author":"Forsman","year":"2008","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e65005","DOI":"10.7554\/eLife.65005","article-title":"Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies","volume":"10","author":"Caillat","year":"2021","journal-title":"eLife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1016\/j.ymthe.2025.03.039","article-title":"An engineered antibody-lectin conjugate targeting the HIV glycan shield protects humanized mice against HIV challenge","volume":"33","author":"Kumariya","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14079","DOI":"10.1073\/pnas.1108777108","article-title":"Designed oligomers of cyanovirin-N show enhanced HIV neutralization","volume":"108","author":"Keeffe","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1089\/088922203322230897","article-title":"Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques","volume":"19","author":"Tsai","year":"2003","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1089\/088922204322749459","article-title":"Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models","volume":"20","author":"Tsai","year":"2004","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1016\/j.ymthe.2019.07.021","article-title":"Engineering of a lectibody targeting high-mannose-type glycans of the HIV envelope","volume":"27","author":"Hamorsky","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1111\/pbi.13090","article-title":"A novel anti-HIV-1 bispecific bNAb-lectin fusion protein engineered in a plant-based transient expression system","volume":"17","author":"Dent","year":"2019","journal-title":"Plant Biotechnol. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8646","DOI":"10.1074\/jbc.M109.034926","article-title":"A lectin isolated from bananas is a potent inhibitor of HIV replication","volume":"285","author":"Swanson","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.str.2017.03.015","article-title":"The tetrameric plant lectin BanLec neutralizes HIV through bidentate binding to specific viral glycans","volume":"25","author":"Hopper","year":"2017","journal-title":"Structure"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"24845","DOI":"10.1074\/jbc.M110.128546","article-title":"Microvirin, a novel alpha(1,2)-mannose-specific lectin isolated from Microcystis aeruginosa, has anti-HIV-1 activity comparable with that of cyanovirin-N but a much higher safety profile","volume":"285","author":"Huskens","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1126\/science.1083182","article-title":"Antibody domain exchange is an immunological solution to carbohydrate cluster recognition","volume":"300","author":"Calarese","year":"2003","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1016\/j.celrep.2013.11.015","article-title":"Structural basis for enhanced HIV-1 neutralization by a dimeric immunoglobulin G form of the glycan-recognizing antibody 2G12","volume":"5","author":"Wu","year":"2013","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10177","DOI":"10.1128\/JVI.01229-14","article-title":"Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV-1 Env by negative-stain single-particle electron microscopy","volume":"88","author":"Murin","year":"2014","journal-title":"J. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9090","DOI":"10.1128\/JVI.01280-15","article-title":"Functional and structural characterization of human V3-specific monoclonal antibody 2424 with neutralizing activity against HIV-1 JRFL","volume":"89","author":"Kumar","year":"2015","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e00805-25","DOI":"10.1128\/spectrum.00805-25","article-title":"Pharmacokinetic-pharmacodynamic modeling of a highly potent and broadly neutralizing anti-CD4 trimeric nanobody to inhibit HIV-1 infection","volume":"13","author":"Fan","year":"2025","journal-title":"Microbiol. Spectr."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Weiss, R.A., and Verrips, C.T. (2019). Nanobodies that neutralize HIV. Vaccines, 7.","DOI":"10.3390\/vaccines7030077"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.str.2022.03.012","article-title":"Structural basis for llama nanobody recognition and neutralization of HIV-1 at the CD4-binding site","volume":"30","author":"Zhou","year":"2022","journal-title":"Structure"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Strokappe, N.M., Hock, M., Rutten, L., McCoy, L.E., Back, J.W., Caillat, C., Haffke, M., Weiss, R.A., Weissenhorn, W., and Verrips, T. (2019). Super potent bispecific llama VHH antibodies neutralize HIV via a combination of gp41 and gp120 Epitopes. Antibodies, 8.","DOI":"10.3390\/antib8020038"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10173","DOI":"10.1128\/JVI.01332-13","article-title":"Heavy chain-only IgG2b llama antibody effects near-pan HIV-1 neutralization by recognizing a CD4-induced epitope that includes elements of coreceptor- and CD4-binding sites","volume":"87","author":"Acharya","year":"2013","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"111795","DOI":"10.1016\/j.isci.2025.111795","article-title":"PET imaging of HIV-1 envelope protein gp120 using (18)F-labeled nanobodies","volume":"28","author":"Shah","year":"2025","journal-title":"iScience"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Strokappe, N., Szynol, A., Aasa-Chapman, M., Gorlani, A., Forsman Quigley, A., Hulsik, D.L., Chen, L., Weiss, R., de Haard, H., and Verrips, T. (2012). Llama antibody fragments recognizing various epitopes of the CD4bs neutralize a broad range of HIV-1 subtypes A, B and C. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033298"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lutje Hulsik, D., Liu, Y.Y., Strokappe, N.M., Battella, S., El Khattabi, M., McCoy, L.E., Sabin, C., Hinz, A., Hock, M., and Macheboeuf, P. (2013). A gp41 MPER-specific llama VHH requires a hydrophobic CDR3 for neutralization but not for antigen recognition. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003202"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"13413","DOI":"10.1038\/s41598-022-15993-y","article-title":"Directing HIV-1 for degradation by non-target cells, using bi-specific single-chain llama antibodies","volume":"12","author":"Stam","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"110958","DOI":"10.1016\/j.isci.2024.110958","article-title":"Inhibition of HIV-1 replication by nanobodies targeting tetraspanin CD9","volume":"27","author":"Umotoy","year":"2024","journal-title":"iScience"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9345","DOI":"10.1074\/jbc.M411122200","article-title":"Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp","volume":"280","author":"Mori","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lusvarghi, S., and Bewley, C.A. (2016). Griffithsin: An antiviral lectin with outstanding therapeutic potential. Viruses, 8.","DOI":"10.3390\/v8100296"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1021\/acsinfecdis.6b00139","article-title":"Binding site geometry and subdomain valency control effects of neutralizing lectins on HIV-1 viral particles","volume":"2","author":"Lusvarghi","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1016\/j.str.2010.05.016","article-title":"Monomerization of viral entry inhibitor griffithsin elucidates the relationship between multivalent binding to carbohydrates and anti-HIV activity","volume":"18","author":"Moulaei","year":"2010","journal-title":"Structure"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1021\/acschembio.1c00990","article-title":"C(3)-Symmetric aromatic core of griffithsin is essential for potent anti-HIV activity","volume":"17","author":"Sun","year":"2022","journal-title":"ACS Chem. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1600-0684.2007.00242.x","article-title":"Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide","volume":"36","author":"Emau","year":"2007","journal-title":"J. Med. Primatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6099","DOI":"10.1073\/pnas.0901506106","article-title":"Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component","volume":"106","author":"Vojdani","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kouokam, J.C., Huskens, D., Schols, D., Johannemann, A., Riedell, S.K., Walter, W., Walker, J.M., Matoba, N., O\u2019Keefe, B.R., and Palmer, K.E. (2011). Investigation of griffithsin\u2019s interactions with human cells confirms its outstanding safety and efficacy profile as a microbicide candidate. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022635"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1128\/AAC.41.7.1521","article-title":"Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: Potential applications to microbicide development","volume":"41","author":"Boyd","year":"1997","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/S0022-3565(24)29588-4","article-title":"Selective interactions of the human immunodeficiency virus-inactivating protein cyanovirin-N with high-mannose oligosaccharides on gp120 and other glycoproteins","volume":"297","author":"Shenoy","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1128\/AAC.45.3.664-672.2001","article-title":"Cyanovirin-N, a potent human immunodeficiency virus-inactivating protein, blocks both CD4-dependent and CD4-independent binding of soluble gp120 (sgp120) to target cells, inhibits sCD4-induced binding of sgp120 to cell-associated CXCR4, and dissociates bound sgp120 from target cells","volume":"45","author":"Mori","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1006\/bbrc.2001.4495","article-title":"Actinohivin, a novel anti-HIV protein from an actinomycete that inhibits syncytium formation: Isolation, characterization, and biological activities","volume":"282","author":"Chiba","year":"2001","journal-title":"Biochem Biophys. Res. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15633","DOI":"10.1073\/pnas.0907572106","article-title":"Mechanism by which the lectin actinohivin blocks HIV infection of target cells","volume":"106","author":"Tanaka","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1128\/AAC.00254-10","article-title":"Actinohivin, a broadly neutralizing prokaryotic lectin, inhibits HIV-1 infection by specifically targeting high-mannose-type glycans on the gp120 envelope","volume":"54","author":"Hoorelbeke","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"18817","DOI":"10.3390\/molecules191118817","article-title":"Banana lectin: A brief review","volume":"19","author":"Singh","year":"2014","journal-title":"Molecules"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.cell.2015.09.056","article-title":"Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity","volume":"163","author":"Swanson","year":"2015","journal-title":"Cell"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1093\/glycob\/cwi083","article-title":"Concanavalin A binding to HIV envelope protein is less sensitive to mutations in glycosylation sites than monoclonal antibody 2G12","volume":"15","author":"Pashov","year":"2005","journal-title":"Glycobiology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"7777","DOI":"10.1128\/JVI.79.12.7777-7784.2005","article-title":"Resistance of human immunodeficiency virus type 1 to the high-mannose binding agents cyanovirin N and concanavalin A","volume":"79","author":"Witvrouw","year":"2005","journal-title":"J. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zhao, X., Fu, C., Sun, L., Feng, H., Xie, P., Wu, M., Tan, X., and Chen, G. (2023). New insight into the concanavalin A-induced apoptosis in hepatocyte of an animal model: Possible involvement of caspase-independent pathway. Molecules, 28.","DOI":"10.3390\/molecules28031312"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Shahid, M., Qadir, A., Yang, J., Ahmad, I., Zahid, H., Mirza, S., Windisch, M.P., and Shahzad-Ul-Hussan, S. (2020). An Engineered microvirin variant with identical structural domains potently inhibits human immunodeficiency virus and hepatitis C virus cellular entry. Viruses, 12.","DOI":"10.3390\/v12020199"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Parajuli, B., Acharya, K., Bach, H.C., Zhang, S., Abrams, C.F., and Chaiken, I. (2025). Monovalent lectin microvirin utilizes hydropathic recognition of HIV-1 Env for inhibition of virus cell infection. Viruses, 17.","DOI":"10.3390\/v17010082"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/nature10696","article-title":"Structure of HIV-1 gp120 V1\/V2 domain with broadly neutralizing antibody PG9","volume":"480","author":"McLellan","year":"2011","journal-title":"Nature"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1126\/science.1175868","article-title":"Structural basis of immune evasion at the site of CD4 attachment on HIV-1 gp120","volume":"326","author":"Chen","year":"2009","journal-title":"Science"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nature05580","article-title":"Structural definition of a conserved neutralization epitope on HIV-1 gp120","volume":"445","author":"Zhou","year":"2007","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1126\/science.1192819","article-title":"Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01","volume":"329","author":"Zhou","year":"2010","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1146\/annurev-immunol-041015-055515","article-title":"Broadly neutralizing antibodies to HIV and their role in vaccine design","volume":"34","author":"Burton","year":"2016","journal-title":"Annu Rev. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6049","DOI":"10.1073\/pnas.1303682110","article-title":"Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody","volume":"110","author":"Scharf","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1016\/j.str.2013.04.015","article-title":"Structural basis for highly effective HIV-1 neutralization by CD4-mimetic miniproteins revealed by 1.5 \u00c5 cocrystal structure of gp120 and M48U1","volume":"21","author":"Acharya","year":"2013","journal-title":"Structure"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1036874","DOI":"10.3389\/fmed.2022.1036874","article-title":"Design of human immunodeficiency virus-1 neutralizing peptides targeting CD4-binding site: An integrative computational biologics approach","volume":"9","author":"Vivekanandan","year":"2022","journal-title":"Front. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1126\/science.1213782","article-title":"Increasing the potency and breadth of an HIV antibody by using structure-based rational design","volume":"334","author":"Diskin","year":"2011","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1128\/JVI.00461-12","article-title":"Straightforward selection of broadly neutralizing single-domain antibodies targeting the conserved CD4 and coreceptor binding sites of HIV-1 gp120","volume":"87","author":"Matz","year":"2013","journal-title":"J. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"114862","DOI":"10.1016\/j.addr.2023.114862","article-title":"Long-acting parenteral drug delivery systems for the treatment of chronic diseases","volume":"198","author":"Jindal","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s40262-021-01005-1","article-title":"Pharmacokinetics and drug-drug interactions of long-acting intramuscular cabotegravir and rilpivirine","volume":"60","author":"Hodge","year":"2021","journal-title":"Clin. Pharmacokinet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1093\/jac\/dkab228","article-title":"Intramuscular and subcutaneous administration of antiretroviral drugs, compared with oral, enhances delivery to lymphoid tissues in BALB\/c mice","volume":"76","author":"Dyavar","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"108163","DOI":"10.1016\/j.ijid.2025.108163","article-title":"Safety, pharmacokinetics, and efficacy of albuvirtide administered by intravenous bolus every 4 weeks in combination with oral dolutegravir in virologically suppressed adults living with HIV: A 24-week study","volume":"162","author":"Fu","year":"2026","journal-title":"Int. J. Infect. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"114895","DOI":"10.1016\/j.jconrel.2026.114895","article-title":"Therapeutic peptides and proteins: Status and developments in drug delivery","volume":"394","author":"Hornsby","year":"2026","journal-title":"J. Control. Release"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1778569","DOI":"10.3389\/fphar.2026.1778569","article-title":"Molecular engineering approaches to half-life extension of therapeutic biomolecules","volume":"17","author":"Wang","year":"2026","journal-title":"Front. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.1016\/j.apsb.2025.10.026","article-title":"Progress in peptide and protein therapeutics: Challenges and strategies","volume":"15","author":"Liu","year":"2025","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1007\/s40262-025-01568-3","article-title":"PEGylated proteins: How much does molecular weight matter?","volume":"64","author":"Fornasari","year":"2025","journal-title":"Clin. Pharmacokinet."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e10600","DOI":"10.1002\/btm2.10600","article-title":"PEGylated therapeutics in the clinic","volume":"9","author":"Gao","year":"2024","journal-title":"Bioeng. Transl. Med."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Wang, C., Cheng, S., Zhang, Y., Ding, Y., Chong, H., Xing, H., Jiang, S., Li, X., and Ma, L. (2019). Long-acting HIV-1 fusion inhibitory peptides and their mechanisms of action. Viruses, 11.","DOI":"10.3390\/v11090811"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ejmech.2016.05.027","article-title":"Enfuvirtide-PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties","volume":"121","author":"Cheng","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e00386-00320","DOI":"10.1128\/JVI.00386-20","article-title":"Polyethylene glycol 40-modified peptide with high therapeutic efficacy in simian-human immunodeficiency virus-acutely infected rhesus monkeys","volume":"94","author":"Li","year":"2020","journal-title":"J. Virol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Fu, S., Zhu, X., Huang, F., and Chen, X. (2025). Anti-PEG antibodies and their biological impact on PEGylated drugs: Challenges and strategies for optimization. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17081074"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2494775","DOI":"10.1080\/10717544.2025.2494775","article-title":"PEGylation technology: Addressing concerns, moving forward","volume":"32","author":"Simberg","year":"2025","journal-title":"Drug Deliv."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"6457","DOI":"10.1021\/acs.langmuir.4c04636","article-title":"Strategies to enhance protein delivery","volume":"41","author":"Zhu","year":"2025","journal-title":"Langmuir"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.2174\/0929867324666170113112759","article-title":"Fc-fusion proteins in therapy: An updated view","volume":"24","author":"Jafari","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"6147","DOI":"10.1128\/AAC.01285-13","article-title":"A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults","volume":"57","author":"Robbie","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fimmu.2015.00039","article-title":"Selection of IgG variants with increased FcRn binding using random and directed mutagenesis: Impact on effector functions","volume":"6","author":"Monnet","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"5031","DOI":"10.1038\/s41467-019-13108-2","article-title":"An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence","volume":"10","author":"Lee","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1038\/s12276-022-00870-5","article-title":"An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies","volume":"54","author":"Ko","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1038\/s41467-024-46321-9","article-title":"Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria","volume":"15","author":"Foss","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.4049\/jimmunol.143.8.2595","article-title":"Studies of aglycosylated chimeric mouse-human IgG. Role of carbohydrate in the structure and effector functions mediated by the human IgG constant region","volume":"143","author":"Tao","year":"1989","journal-title":"J. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1007\/s12033-012-9612-x","article-title":"With or without sugar? (A)glycosylation of therapeutic antibodies","volume":"54","author":"Hristodorov","year":"2013","journal-title":"Mol. Biotechnol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.4049\/jimmunol.157.11.4963","article-title":"Multiple interactions of IgG with its core oligosaccharide can modulate recognition by complement and human Fc gamma receptor I and influence the synthesis of its oligosaccharide chains","volume":"157","author":"Lund","year":"1996","journal-title":"J. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"183ra57","DOI":"10.1126\/scitranslmed.3005338","article-title":"Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier","volume":"5","author":"Couch","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1111\/imr.13379","article-title":"Living in LALA land? Forty years of attenuating Fc effector functions","volume":"328","author":"Hale","year":"2024","journal-title":"Immunol. Rev."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"9036","DOI":"10.1073\/pnas.88.20.9036","article-title":"Identification of the Fc gamma receptor class I binding site in human IgG through the use of recombinant IgG1\/IgG2 hybrid and point-mutated antibodies","volume":"88","author":"Chappel","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3900","DOI":"10.1074\/jbc.M116.767749","article-title":"Effector-attenuating substitutions that maintain antibody stability and reduce toxicity in mice","volume":"292","author":"Lo","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/protein\/gzw040","article-title":"Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions","volume":"29","author":"Schlothauer","year":"2016","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1107\/S0907444908007877","article-title":"Structural characterization of a human Fc fragment engineered for lack of effector functions","volume":"64","author":"Oganesyan","year":"2008","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.xphs.2016.12.023","article-title":"An \"Fc-silenced\" IgG1 format with extended half-life designed for improved stability","volume":"106","author":"Borrok","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2152526","DOI":"10.1080\/19420862.2022.2152526","article-title":"Developability profiling of a panel of Fc engineered SARS-CoV-2 neutralizing antibodies","volume":"15","author":"Dippel","year":"2023","journal-title":"mAbs"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/s42003-021-01790-2","article-title":"Programmable half-life and anti-tumour effects of bispecific T-cell engager-albumin fusions with tuned FcRn affinity","volume":"4","author":"Mandrup","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"34583","DOI":"10.1074\/jbc.M114.587675","article-title":"Interaction with both domain I and III of albumin is required for optimal pH-dependent binding to the neonatal Fc receptor (FcRn)","volume":"289","author":"Sand","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"146933","DOI":"10.1016\/j.ijbiomac.2025.146933","article-title":"Single-chain variable fragments targeting domain II of human serum albumin for enhanced circulatory half-life via albumin association","volume":"322","author":"Park","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"5234","DOI":"10.1074\/jbc.M110.164848","article-title":"Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain","volume":"286","author":"Andersen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e557","DOI":"10.1002\/mco2.557","article-title":"Half-life extension of single-domain antibody-drug conjugates by albumin binding moiety enhances antitumor efficacy","volume":"5","author":"Li","year":"2024","journal-title":"MedComm"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.actbio.2025.11.017","article-title":"Harnessing albumin as a carrier for the delivery of anti-HIV drugs to the lymphatic system","volume":"209","author":"Zhang","year":"2026","journal-title":"Acta Biomater."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1128\/AAC.00976-09","article-title":"An albumin-conjugated peptide exhibits potent anti-HIV activity and long in vivo half-life","volume":"54","author":"Xie","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.bbagen.2011.09.009","article-title":"The intracellular trafficking pathway of transferrin","volume":"1820","author":"Mayle","year":"2012","journal-title":"Biochim Biophys. Acta"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1124\/jpet.110.166470","article-title":"Transferrin fusion technology: A novel approach to prolonging biological half-life of insulinotropic peptides","volume":"334","author":"Kim","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1038\/s41467-025-57108-x","article-title":"Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution","volume":"16","author":"Khoury","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"110995","DOI":"10.1016\/j.jbc.2025.110995","article-title":"A humanized transferrin receptor 1-transferrin model supports functional iron homeostasis and therapeutic delivery across the blood-brain barrier","volume":"302","author":"Yesiltepe","year":"2026","journal-title":"J. Biol. Chem."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1517\/17425255.2012.673585","article-title":"Pharmacokinetics of recombinant bifunctional fusion proteins","volume":"8","author":"Chen","year":"2012","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.addr.2003.07.004","article-title":"Mechanisms of TfR-mediated transcytosis and sorting in epithelial cells and applications toward drug delivery","volume":"55","author":"Widera","year":"2003","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jconrel.2009.09.007","article-title":"Human growth hormone-transferrin fusion protein for oral delivery in hypophysectomized rats","volume":"141","author":"Amet","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"4421","DOI":"10.4049\/jimmunol.163.8.4421","article-title":"An antibody-avidin fusion protein specific for the transferrin receptor serves as a delivery vehicle for effective brain targeting: Initial applications in anti-HIV antisense drug delivery to the brain","volume":"163","author":"Penichet","year":"1999","journal-title":"J. Immunol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s40259-015-0133-6","article-title":"Fusion proteins for half-life extension of biologics as a strategy to make biobetters","volume":"29","author":"Strohl","year":"2015","journal-title":"BioDrugs"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1097\/MS9.0000000000004783","article-title":"Lenacapavir and global HIV prevention: A breakthrough at risk of leaving millions behind","volume":"88","author":"Miteu","year":"2026","journal-title":"Ann. Med. Surg."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/imr.12506","article-title":"HIV antibodies for treatment of HIV infection","volume":"275","author":"Margolis","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/COH.0000000000000644","article-title":"Roles of fragment crystallizable-mediated effector functions in broadly neutralizing antibody activity against HIV","volume":"15","author":"Danesh","year":"2020","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"18754","DOI":"10.1073\/pnas.2008236117","article-title":"Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody","volume":"117","author":"Asokan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/imr.13383","article-title":"Antibody-mediated control mechanisms of viral infections","volume":"328","author":"Mackin","year":"2024","journal-title":"Immunol. Rev."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.cell.2014.08.023","article-title":"Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity","volume":"158","author":"Bournazos","year":"2014","journal-title":"Cell"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1073\/pnas.0508123103","article-title":"Engineered antibody Fc variants with enhanced effector function","volume":"103","author":"Lazar","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41586-020-2838-z","article-title":"Fc-optimized antibodies elicit CD8 immunity to viral respiratory infection","volume":"588","author":"Bournazos","year":"2020","journal-title":"Nature"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"929895","DOI":"10.3389\/fimmu.2022.929895","article-title":"Role of Fc core fucosylation in the effector function of IgG1 antibodies","volume":"13","author":"Golay","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1080\/19420862.2018.1466767","article-title":"The \u201cless-is-more\u201d in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity","volume":"10","author":"Pereira","year":"2018","journal-title":"mAbs"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1111\/j.1365-2443.2011.01552.x","article-title":"Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans","volume":"16","author":"Mizushima","year":"2011","journal-title":"Genes Cells"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"106015","DOI":"10.1016\/j.antiviral.2024.106015","article-title":"Functional comparison of Fc-engineering strategies to improve anti-HIV-1 antibody effector functions","volume":"231","author":"Schriek","year":"2024","journal-title":"Antivir. Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1038\/s42003-024-06659-8","article-title":"Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing","volume":"7","author":"Schriek","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"qiaf033","DOI":"10.1093\/jleuko\/qiaf033","article-title":"Afucosylated broadly neutralizing antibodies targeting the HIV envelope elicit enhanced NK-cell-mediated cytotoxicity against HIV-infected CD4+ T-cell and macrophage targets","volume":"117","author":"Wilhelm","year":"2025","journal-title":"J. Leukoc. Biol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2613548","DOI":"10.1080\/19420862.2026.2613548","article-title":"The making of multispecific immunoglobulins\u2014A clinical perspective","volume":"18","author":"Brinkmann","year":"2026","journal-title":"mAbs"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1783276","DOI":"10.3389\/fimmu.2026.1783276","article-title":"Advancing immunotherapy via multiple immune cells co-engagement","volume":"17","author":"Li","year":"2026","journal-title":"Front. Immunol."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1002\/cbic.202000261","article-title":"Multivalent antibody-recruiting macromolecules: Linking increased binding affinity with enhanced innate immune killing","volume":"21","author":"Uvyn","year":"2020","journal-title":"ChemBioChem"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"5654","DOI":"10.1038\/s41467-022-32867-z","article-title":"Circulating multimeric immune complexes contribute to immunopathology in COVID-19","volume":"13","author":"Ankerhold","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"2505092","DOI":"10.1080\/19420862.2025.2505092","article-title":"Impact of antibody Fc engineering on translational pharmacology, and safety: Insights from industry case studies","volume":"17","author":"Brennan","year":"2025","journal-title":"mAbs"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"e2724","DOI":"10.1002\/btpr.2724","article-title":"Transient CHO expression platform for robust antibody production and its enhanced N-glycan sialylation on therapeutic glycoproteins","volume":"35","author":"Zhong","year":"2019","journal-title":"Biotechnol. Prog."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/0958-1669(95)80092-1","article-title":"Production of monoclonal antibodies in COS and CHO cells","volume":"6","author":"Trill","year":"1995","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_159","first-page":"30","article-title":"Augmenting recombinant antibody production in HEK293E cells: Optimizing transfection and culture parameters","volume":"5","author":"Heng","year":"2022","journal-title":"Antib. Ther."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12575-017-0060-7","article-title":"Efficient and inexpensive transient expression of multispecific multivalent antibodies in Expi293 cells","volume":"19","author":"Fang","year":"2017","journal-title":"Biol. Proced. Online"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"e11165","DOI":"10.7717\/peerj.11165","article-title":"Transfection types, methods and strategies: A technical review","volume":"9","author":"Chong","year":"2021","journal-title":"PeerJ"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"131126","DOI":"10.1016\/j.jhazmat.2023.131126","article-title":"Rapid generation of high-quality recombinant antibodies using an Expi293F expression system for a 17 beta-estradiol immunoassay","volume":"451","author":"Lu","year":"2023","journal-title":"J. Hazard Mater."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1661193","DOI":"10.3389\/fbioe.2025.1661193","article-title":"Updated transient gene expression protocol in Expi293F cells using PEI","volume":"13","author":"Hederoth","year":"2025","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1002\/bit.22265","article-title":"High-level protein expression in scalable CHO transient transfection","volume":"103","author":"Ye","year":"2009","journal-title":"Biotechnol. Bioeng."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.nbt.2024.08.499","article-title":"Production and characterization of novel anti-HIV Fc-fusion proteins in plant-based systems: Nicotiana benthamiana & tobacco BY-2 cell suspension","volume":"83","author":"Cunyat","year":"2024","journal-title":"New Biotechnol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0022-1759(99)00002-2","article-title":"Production of secreted, soluble human two-domain CD4 protein in Escherichia coli","volume":"224","author":"Osburne","year":"1999","journal-title":"J. Immunol. Methods"},{"key":"ref_167","first-page":"1","article-title":"Challenges and solutions for the downstream purification of therapeutic proteins","volume":"7","author":"Tang","year":"2024","journal-title":"Antib. Ther."},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Withanage, T.J., Alcalay, R., Krichevsky, O., Wachtel, E., Mazor, O., and Patchornik, G. (2025). Purification of a Fc-fusion protein with [bathophenathroline:metal] complexes. Antibodies, 14.","DOI":"10.3390\/antib14010011"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1093\/protein\/9.7.617","article-title":"Knobs-into-holes\u2019 engineering of antibody CH3 domains for heavy chain heterodimerization","volume":"9","author":"Ridgway","year":"1996","journal-title":"Protein Eng."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"231","DOI":"10.4161\/19420862.2015.989013","article-title":"Production of bispecific antibodies in \u201cknobs-into-holes\u201d using a cell-free expression system","volume":"7","author":"Xu","year":"2015","journal-title":"mAbs"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2483272","DOI":"10.1080\/19420862.2025.2483272","article-title":"Rapid affinity-based purification of multi-specific antibodies using kappa select and protein L","volume":"17","author":"Mix","year":"2025","journal-title":"mAbs"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s40643-022-00562-y","article-title":"Excellent removal of knob-into-hole bispecific antibody byproducts and impurities in a single-capture chromatography","volume":"9","author":"Chen","year":"2022","journal-title":"Bioresour. Bioprocess"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1080\/19420862.2016.1160192","article-title":"Development of purification processes for fully human bispecific antibodies based upon modification of protein A binding avidity","volume":"8","author":"Tustian","year":"2016","journal-title":"mAbs"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"105847","DOI":"10.1016\/j.pep.2021.105847","article-title":"Removing a single-arm species by Fibro PrismA in purifying an asymmetric IgG-like bispecific antibody","volume":"182","author":"Zhang","year":"2021","journal-title":"Protein Expr. Purif."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41577-023-00858-w","article-title":"Antiviral neutralizing antibodies: From in vitro to in vivo activity","volume":"23","author":"Burton","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"e00372-19","DOI":"10.1128\/JVI.00372-19","article-title":"Simian-human immunodeficiency virus SHIV.CH505 infection of rhesus macaques results in persistent viral replication and induces intestinal immunopathology","volume":"93","author":"Bar","year":"2019","journal-title":"J. Virol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"112255","DOI":"10.1016\/j.celrep.2023.112255","article-title":"Neonatal SHIV infection in rhesus macaques elicited heterologous HIV-1-neutralizing antibodies","volume":"42","author":"Hora","year":"2023","journal-title":"Cell Rep."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/0300985820948822","article-title":"Human CD34(+) Hematopoietic stem cell-engrafted NSG mice: Morphological and immunophenotypic features","volume":"58","author":"Blumich","year":"2021","journal-title":"Vet. Pathol."},{"key":"ref_179","unstructured":"Pebody, R.S. (2026, August 09). Recommended Treatments for HIV 2026. Available online: https:\/\/www.aidsmap.com\/about-hiv\/recommended-treatments-hiv."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1221\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:26:25Z","timestamp":1787559985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1221"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,22]]},"references-count":179,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biom16091221"],"URL":"https:\/\/doi.org\/10.3390\/biom16091221","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,22]]}}}