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The symptoms of leishmaniasis include high fever and weakness, and the cutaneous infection also causes lesions under the skin. The drugs used to treat leishmaniasis have become less effective due to the resistance mechanisms of the protozoa. In addition, the current compounds have low selectivity for the pathogen, leading to various side effects, which results in lower adherence to treatment. Various strategies were developed to solve this problem. The bioconjugation between natural compounds with antimicrobial activity and cell-penetrating peptides could alleviate the resistance and toxicity of current treatments. This work aims to conjugate the cell penetration peptide TAT to the guanidine GVL1. The GVL1-TAT bioconjugate exhibited leishmanicidal activity against Leishmania amazonensis and Leishmania infantum with a high selectivity index. In addition, the bioconjugate was more active against the intracellular enzyme CPP than the individual compounds. This target is very important for the viability and virulence of the parasite within the host cell. Docking studies confirmed the higher interaction of the conjugate with CPP and suggested that other proteins, such as trypanothione reductase, could be targeted. Thus, the data indicated that guanidines conjugated with cell-penetrating peptides could be a good approach for developing antileishmanial molecules.<\/jats:p>","DOI":"10.3390\/molecules30020264","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T05:40:40Z","timestamp":1736746840000},"page":"264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Guanidines Conjugated with Cell-Penetrating Peptides: A New Approach for the Development of Antileishmanial Molecules"],"prefix":"10.3390","volume":"30","author":[{"given":"Jo\u00e3o Victor Marcelino","family":"de Souza","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Organic Chemistry, Institute of Chemistry, S\u00e3o Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7250-4908","authenticated-orcid":false,"given":"Natalia C. S.","family":"Costa","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C. O. Arruda","family":"Brasil","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Organic Chemistry, Institute of Chemistry, S\u00e3o Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2487-6176","authenticated-orcid":false,"given":"Luana Ribeiro","family":"dos Anjos","sequence":"additional","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2718-4914","authenticated-orcid":false,"given":"Renata Priscila Barros","family":"de Menezes","sequence":"additional","affiliation":[{"name":"Natural Products and Synthetic Bioactives Postgraduation Program, Federal Paraiba University (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4547-693X","authenticated-orcid":false,"given":"Eduardo Henrique","family":"Zampieri","sequence":"additional","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-5487","authenticated-orcid":false,"given":"Jhonatan Santos","family":"de Lima","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela Maria Arenas","family":"Velasquez","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-4107","authenticated-orcid":false,"given":"Luciana","family":"Scotti","sequence":"additional","affiliation":[{"name":"Natural Products and Synthetic Bioactives Postgraduation Program, Federal Paraiba University (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-8057","authenticated-orcid":false,"given":"Marcus Tullius","family":"Scotti","sequence":"additional","affiliation":[{"name":"Natural Products and Synthetic Bioactives Postgraduation Program, Federal Paraiba University (UFPB), Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7280-3775","authenticated-orcid":false,"given":"Marcia A. S.","family":"Graminha","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1348-8554","authenticated-orcid":false,"given":"Eduardo R. P\u00e9rez","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Fine Organic Chemistry Lab, School of Sciences and Technology, S\u00e3o Paulo State University (UNESP), Presidente Prudente 19060-080, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4767-0904","authenticated-orcid":false,"given":"Eduardo Maffud","family":"Cilli","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Organic Chemistry, Institute of Chemistry, S\u00e3o Paulo State University (UNESP), Araraquara 14800-060, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"ref_1","first-page":"1000166","article-title":"A Review on Biology, Epidemiology and Public Health Significance of Leishmaniasis","volume":"4","author":"Dawit","year":"2013","journal-title":"J. Bacteriol. Parasitol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s40475-021-00232-7","article-title":"A Review of Leishmaniasis: Current Knowledge and Future Directions","volume":"8","author":"Mann","year":"2021","journal-title":"Curr. Trop. Med. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1007\/s00104-019-0994-1","article-title":"Visceral Leishmaniasis","volume":"90","author":"Wilhelm","year":"2019","journal-title":"Die Chir."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1128\/AAC.00030-11","article-title":"Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani","volume":"56","author":"Purkait","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ponte-Sucre, A., Gamarro, F., Dujardin, J.C., Barrett, M.P., L\u00f3pez-V\u00e9lez, R., Garc\u00eda-Hern\u00e1ndez, R., Pountain, A.W., Mwenechanya, R., and Papadopoulou, B. (2017). Drug Resistance and Treatment Failure in Leishmaniasis: A 21st Century Challenge. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0006052"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/18755305MTAwENDE80","article-title":"Mini Review on Antimicrobial Peptides, Sources, Mechanism and Recent Applications","volume":"27","author":"Boparai","year":"2020","journal-title":"Protein Pept. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.addr.2012.10.014","article-title":"Polymer-Drug Conjugates: Origins, Progress to Date and Future Directions","volume":"65","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Tassone, G., Mazzorana, M., and Pozzi, C. (2022). Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules. Pharmaceuticals, 15.","DOI":"10.3390\/ph15111341"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1021\/acs.jnatprod.6b00256","article-title":"Analogues of Marine Guanidine Alkaloids are In Vitro Effective Against Trypanosoma cruzi and Selectively Eliminate Leishmania (L.) infantum Intracellular Amastigotes","volume":"79","author":"Martins","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"116162","DOI":"10.1016\/j.ejmech.2024.116162","article-title":"Novel Aroyl Guanidine Anti-Trypanosomal Compounds that Exert Opposing Effects on Parasite Energy Metabolism","volume":"268","author":"Varghese","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ejmech.2019.03.032","article-title":"N, N\u2019, N\u2033-Trisubstituted Guanidines: Synthesis, Characterization and Evaluation of Their Leishmanicidal Activity","volume":"171","author":"Passianoto","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1039\/C7NP00037E","article-title":"The Chemistry and Biology of Guanidine Natural Products","volume":"34","author":"Berlinck","year":"2017","journal-title":"Nat. Prod. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Moreira, V.P., da Silva Mela, M.F., Anjos, L.R.D., Saraiva, L.F., Arenas Vel\u00e1squez, A.M., Kalaba, P., Fabisikov\u00e1, A., Clementino, L.D.C., Aufy, M., and Studenik, C. (2022). Novel Selective and Low-Toxic Inhibitor of LmCPB2.8\u0394CTE (CPB) One Important Cysteine Protease for Leishmania Virulence. Biomolecules, 12.","DOI":"10.3390\/biom12121903"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Rawat, A., Roy, M., Jyoti, A., Kaushik, S., Verma, K., and Srivastava, V.K. (2021). Cysteine Proteases: Battling Pathogenic Parasitic Protozoans with Omnipresent Enzymes. Microbiol. Res., 249.","DOI":"10.1016\/j.micres.2021.126784"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6794","DOI":"10.4049\/jimmunol.161.12.6794","article-title":"Leishmania mexicana Cysteine Proteinase-Deficient Mutants Have Attenuated Virulence for Mice and Potentiate a Th1 Response","volume":"161","author":"Alexander","year":"1998","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34008","DOI":"10.1021\/acsomega.3c04878","article-title":"Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines","volume":"8","author":"Costa","year":"2023","journal-title":"ACS Omega"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Miwa, A., and Kamiya, K. (2024). Cell-Penetrating Peptide-Mediated Biomolecule Transportation in Artificial Lipid Vesicles and Living Cells. Molecules, 29.","DOI":"10.3390\/molecules29143339"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/1742-4690-6-74","article-title":"Mechanism of HIV-1 Tat RNA Translation and Its Activation by the Tat Protein","volume":"6","author":"Charnay","year":"2009","journal-title":"Retrovirology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1016\/j.bbamem.2017.09.015","article-title":"Fluorophore Labeling of a Cell-Penetrating Peptide Induces Differential Effects on Its Cellular Distribution and Affects Cell Viability","volume":"1859","author":"Birch","year":"2017","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/14712598.2021.1823368","article-title":"Status Update in the Use of Cell-Penetrating Peptides for the Delivery of Macromolecular Therapeutics","volume":"21","author":"Kurrikoff","year":"2021","journal-title":"Expert. Opin. Biol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Illa, O., Olivares, J.A., Gaztelumendi, N., Mart\u00ednez-Castro, L., Ospina, J., Abengozar, M., Sciortino, G., Mar\u00e9chal, J.D., Nogu\u00e9s, C., and Royo, M. (2020). Chiral Cyclobutane-Containing Cell-Penetrating Peptides as Selective Vectors for Anti-Leishmania Drug Delivery Systems. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207502"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1007\/s00726-013-1661-3","article-title":"A BODIPY-Embedding Miltefosine Analog Linked to Cell-Penetrating Tat(48-60) Peptide Favors Intracellular Delivery and Visualization of the Antiparasitic Drug","volume":"46","author":"Hornillos","year":"2014","journal-title":"Amino Acids"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s40257-022-00726-8","article-title":"Cutaneous Leishmaniasis: A 2022 Updated Narrative Review into Diagnosis and Management Developments","volume":"23","author":"Schallig","year":"2022","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"588","DOI":"10.3855\/jidc.6833","article-title":"Recent Updates and Perspectives on Leishmaniasis","volume":"9","author":"Savoia","year":"2015","journal-title":"J. Infect. Dev. Ctries."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41579-022-00777-y","article-title":"Anti-Trypanosomatid Drug Discovery: Progress and Challenges","volume":"21","author":"Wyllie","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1080\/14656566.2019.1609940","article-title":"Current and Emerging Medications for the Treatment of Leishmaniasis","volume":"20","author":"Chakravarty","year":"2019","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1046\/j.1365-3156.2001.00778.x","article-title":"Drug Resistance in Indian Visceral Leishmaniasis","volume":"6","author":"Sundar","year":"2001","journal-title":"Trop. Med. Int. Health"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.2174\/156802662032201118092318","article-title":"Peptide Therapeutics: Scientific Approaches, Current Development Trends, and Future Directions","volume":"20","author":"Qvit","year":"2020","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Raja, Z., Andr\u00e9, S., Abbassi, F., Humblot, V., Lequin, O., Bouceba, T., Correia, I., Casale, S., Foulon, T., and Sereno, D. (2017). Insight into the Mechanism of Action of Temporin-SHa, a New Broad-Spectrum Antiparasitic and Antibacterial Agent. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174024"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107934","DOI":"10.1016\/j.exppara.2020.107934","article-title":"A Natural Cell-Penetrating Nanopeptide Combined with Pentavalent Antimonial as Experimental Therapy Against Cutaneous Leishmaniasis","volume":"217","author":"Ferreira","year":"2020","journal-title":"Exp. Parasitol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Cruz, G.S., Santos, A.T.D., Brito, E.H.S., and R\u00e1dis-Baptista, G. (2022). Cell-Penetrating Antimicrobial Peptides with Anti-Infective Activity Against Intracellular Pathogens. Antibiotics, 11.","DOI":"10.3390\/antibiotics11121772"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Oualha, R., Barhoumi, M., Marzouki, S., Harigua-Souiai, E., Ben Ahmed, M., and Guizani, I. (2019). Infection of Human Neutrophils with Leishmania infantum or Leishmania major Strains Triggers Activation and Differential Cytokines Release. Front. Cell Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00153"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1021\/acs.bioconjchem.3c00147","article-title":"Development of Antiplasmodial Peptide-Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells","volume":"34","author":"Palombi","year":"2023","journal-title":"Bioconjug. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1016\/S1473-3099(23)00353-5","article-title":"The Status of Combination Therapy for Visceral Leishmaniasis: An Updated Review","volume":"24","author":"Dorlo","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113712","DOI":"10.1016\/j.ejmech.2021.113712","article-title":"Source and Exploration of the Peptides Used to Construct Peptide-Drug Conjugates","volume":"224","author":"Zhou","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mahlapuu, M., H\u00e5kansson, J., Ringstad, L., and Bj\u00f6rn, C. (2016). Antimicrobial Peptides: An Emerging Category of Therapeutic Agents. Front. Cell Infect. Microbiol., 6.","DOI":"10.3389\/fcimb.2016.00194"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"98","DOI":"10.2174\/0929866526666190102125304","article-title":"Dimerization of Antimicrobial Peptides: A Promising Strategy to Enhance Antimicrobial Peptide Activity","volume":"26","author":"Lorenzon","year":"2019","journal-title":"Protein Pept. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Santos, C., Rodrigues, G.R., Lima, L.F., Dos Reis, M.C.G., Cunha, N.B., Dias, S.C., and Franco, O.L. (2022). Advances and Perspectives for Antimicrobial Peptide and Combinatory Therapies. Front. Bioeng. Biotechnol., 10.","DOI":"10.3389\/fbioe.2022.1051456"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Talapko, J., Me\u0161trovi\u0107, T., Juzba\u0161i\u0107, M., Tomas, M., Eri\u0107, S., Horvat Aleksijevi\u0107, L., Beki\u0107, S., Schwarz, D., Mati\u0107, S., and Neuberg, M. (2022). Antimicrobial Peptides-Mechanisms of Action, Antimicrobial Effects and Clinical Applications. Antibiotics, 11.","DOI":"10.3390\/antibiotics11101417"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1071\/CH19449","article-title":"The Mechanism of Membrane Permeabilization by Peptides: Still an Enigma","volume":"73","author":"Wimley","year":"2019","journal-title":"Aust. J. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.4049\/jimmunol.173.5.3297","article-title":"Inhibition of Lipopolysaccharide-Induced Macrophage IL-12 Production by Leishmania mexicana Amastigotes: The Role of Cysteine Peptidases and the NF-kappaB Signaling Pathway","volume":"173","author":"Cameron","year":"2004","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Clementino, L.D.C., Fernandes, G.F.S., Prokopczyk, I.M., Laurindo, W.C., Toyama, D., Motta, B.P., Baviera, A.M., Henrique-Silva, F., Santos, J.L.D., and Graminha, M.A.S. (2021). Design, Synthesis and Biological Evaluation of N-Oxide Derivatives with Potent In Vivo Antileishmanial Activity. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0259008"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.mib.2004.06.010","article-title":"Cysteine Peptidases as Virulence Factors of Leishmania","volume":"7","author":"Mottram","year":"2004","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.4049\/jimmunol.170.4.1746","article-title":"The Leishmania mexicana Cysteine Protease, CPB2.8, Induces Potent Th2 Responses","volume":"170","author":"Pollock","year":"2003","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1046\/j.1523-1747.2003.12132.x","article-title":"Antimicrobial and Protease Inhibitory Functions of the Human Cathelicidin (hCAP18\/LL-37) Prosequence","volume":"120","author":"Zaiou","year":"2003","journal-title":"J. Invest. Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Carneiro, P.P., Concei\u00e7\u00e3o, J., Macedo, M., Magalh\u00e3es, V., Carvalho, E.M., and Bacellar, O. (2016). The Role of Nitric Oxide and Reactive Oxygen Species in the Killing of Leishmania braziliensis by Monocytes from Patients with Cutaneous Leishmaniasis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0148084"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s12026-007-8012-y","article-title":"L-Arginine Metabolism and Its Impact on Host Immunity Against Leishmania Infection","volume":"41","author":"Wanasen","year":"2008","journal-title":"Immunol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.biochi.2022.12.010","article-title":"Assessing the Effect of Antimony Pressure on Trypanothione Reductase Activity in Leishmania (Viannia) braziliensis","volume":"208","author":"Miranda","year":"2023","journal-title":"Biochimie"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.molbiopara.2007.11.002","article-title":"Divergence of Trypanothione-Dependent Tryparedoxin Cascade into Cytosolic and Mitochondrial Pathways in Arsenite-Resistant Variants of Leishmania amazonensis","volume":"157","author":"Hsu","year":"2008","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1021\/acsinfecdis.3c00589","article-title":"Nature-Inspired Gallinamides Are Potent Antischistosomal Agents: Inhibition of the Cathepsin B1 Protease Target and Binding Mode Analysis","volume":"10","author":"Horn","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Maveyraud, L., and Mourey, L. (2020). Protein X-ray Crystallography and Drug Discovery. Molecules, 25.","DOI":"10.3390\/molecules25051030"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ros-Lucas, A., Martinez-Peinado, N., Bastida, J., Gasc\u00f3n, J., and Alonso-Padilla, J. (2022). The Use of AlphaFold for In Silico Exploration of Drug Targets in the Parasite Trypanosoma cruzi. Front. Cell Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.944748"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0020-7519(03)00010-9","article-title":"Cloning and Characterisation of a Cysteine Proteinase Gene Expressed in Amastigotes of Leishmania (L.) amazonensis","volume":"33","author":"Lasakosvitsch","year":"2003","journal-title":"Int. J. Parasitol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Possart, K., Herrmann, F.C., Jose, J., and Schmidt, T.J. (2023). In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase. Molecules, 28.","DOI":"10.3390\/molecules28227526"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Bora, K., Sarma, M., Kanaujia, S.P., and Dubey, V.K. (2023). Dual-Target Drugs Against Leishmania donovani for Potential Novel Therapeutics. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-45448-x"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Battista, T., Colotti, G., Ilari, A., and Fiorillo, A. (2020). Targeting Trypanothione Reductase, a Key Enzyme in the Redox Trypanosomatid Metabolism, to Develop New Drugs Against Leishmaniasis and Trypanosomiases. Molecules, 25.","DOI":"10.3390\/molecules25081924"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fiorillo, A., Colotti, G., Exertier, C., Liuzzi, A., Seghetti, F., Salerno, A., Caciolla, J., and Ilari, A. (2022). Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design. Front. Mol. Biosci., 9.","DOI":"10.3389\/fmolb.2022.900882"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1021\/bi00897a032","article-title":"Solid-Phase Peptide Synthesis. 3. An Improved Synthesis of Bradykinin","volume":"3","author":"Merrifield","year":"1964","journal-title":"Biochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e00688-17","DOI":"10.1128\/AAC.00688-17","article-title":"Efficacy of a Binuclear Cyclopalladated Compound Therapy for Cutaneous Leishmaniasis in the Murine Model of Infection with Leishmania amazonensis and Its Inhibitory Effect on Topoisomerase 1B","volume":"61","author":"Ribeiro","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.biopha.2017.08.096","article-title":"In Vivo Antileishmanial Activity and histopathological Evaluation in Leishmania infantum Infected Hamsters After Treatment with a Furoxan Derivative","volume":"95","author":"Passalacqua","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e0076721","DOI":"10.1128\/AAC.00767-21","article-title":"New Insights into the Mechanism of Action of the Cyclopalladated Complex (CP2) in Leishmania: Calcium Dysregulation, Mitochondrial Dysfunction, and Cell Death","volume":"66","author":"Bartlett","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1007\/s00726-014-1832-x","article-title":"Interaction Between the Antimicrobial Peptide Aurein 1.2 Dimer and Mannans","volume":"46","author":"Piccoli","year":"2014","journal-title":"Amino Acids"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Coudert, E., Gehant, S., de Castro, E., Pozzato, M., Baratin, D., Neto, T., Sigrist, C.J.A., Redaschi, N., Bridge, A., and Consortium, U. (2023). Annotation of Biologically Relevant Ligands in UniProtKB Using ChEBI. Bioinformatics, 39.","DOI":"10.1101\/2022.08.19.504519"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/nar\/gkac305","article-title":"ProteinsPlus: A Comprehensive Collection of Web-Based Molecular Modeling Tools","volume":"50","author":"Diedrich","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1021\/acs.jcim.3c00336","article-title":"Binding Site Detection Remastered: Enabling Fast, Robust, and Reliable Binding Site Detection and Descriptor Calculation with DoGSite3","volume":"63","author":"Graef","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1021\/ci100241y","article-title":"Analyzing the Topology of Active Sites: On the Prediction of Pockets and Subpockets","volume":"50","author":"Volkamer","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_67","unstructured":"Company C (2013). Bio Molegro Virtual Docker-User Manual, CLC Bio Company."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1021\/jm051197e","article-title":"MolDock: A New Technique for High-Accuracy Molecular Docking","volume":"49","author":"Thomsen","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. Model."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/2\/264\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:26:47Z","timestamp":1759919207000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/2\/264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,10]]},"references-count":69,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["molecules30020264"],"URL":"https:\/\/doi.org\/10.3390\/molecules30020264","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,10]]}}}