{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:36:20Z","timestamp":1791844580142,"version":"4.3.4"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"24","license":[{"start":{"date-parts":[[2015,12,15]],"date-time":"2015-12-15T00:00:00Z","timestamp":1450137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,12,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>The peptide drug enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but it easily induces drug resistance, calling for new strategies for developing effective drugs. On the basis of the M-T hook structure, we recently developed highly potent short-peptide HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the conserved gp41 pocket and possess high genetic barriers to resistance. Here, we focused on the selection and characterization of HIV-1 escape mutants of MTSC22, which revealed new resistance pathways and mechanisms. Two mutations (E49K and L57R) located at the inhibitor-binding site and two mutations (N126K and E136G) located at the C-terminal heptad repeat region of gp41 were identified as conferring high resistance either singly or in combination. While E49K reduced the C-terminal binding of inhibitors via an electrostatic repulsion, L57R dramatically disrupted the N-terminal binding of M-T hook structure and pocket-binding domain. Unlike E49K and N126K, which enhanced the stability of the endogenous viral six-helical bundle core (6-HB), L57R and E136G conversely destabilized the 6-HB structure. We also demonstrated that both primary and secondary mutations caused the structural changes in 6-HB and severely impaired the capability for HIV-1 entry. Collectively, our data provide novel insights into the mechanisms of short-peptide fusion inhibitors targeting the gp41 pocket site and help increase our understanding of the structure and function of gp41 and HIV-1 evolution.<\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The deep pocket on the N-trimer of HIV-1 gp41 has been considered an ideal drug target because of its high degree of conservation and essential role in viral entry. Short-peptide fusion inhibitors, which contain an M-T hook structure and mainly target the pocket site, show extremely high binding and inhibitory activities as well as high genetic barriers to resistance. In this study, the HIV-1 mutants resistant to MTSC22 were selected and characterized, which revealed that the E49K and L57R substitutions at the inhibitor-binding site and the N126K and E136G substitutions at the C-terminal heptad repeat region of gp41 critically determine the resistance phenotype. The data provide novel insights into the mechanisms of action of the M-T hook structure-based fusion inhibitors which will help further our understanding of the structure-function relationship of gp41 and molecular pathways of HIV-1 evolution and eventually facilitate the development of new anti-HIV drugs.\n          <\/jats:p>","DOI":"10.1128\/jvi.01741-15","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T02:18:53Z","timestamp":1444270733000},"page":"12467-12479","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Genetic Pathway of HIV-1 Resistance to Novel Fusion Inhibitors Targeting the Gp41 Pocket"],"prefix":"10.1128","volume":"89","author":[{"given":"Yang","family":"Su","sequence":"first","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihiui","family":"Chong","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengwen","family":"Xiong","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Qiao","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonglin","family":"Qiu","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxian","family":"He","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences &amp; Peking Union Medical College, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80205-6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12303"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/387426a0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161210794079218"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.2174\/1381612811319100004"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.22.12428-12437.2004"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkh330"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.2.764-770.2005"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.3.1113-1119.2005"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e3280102377"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02413-06"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1086\/587693"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2011.06.020"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00352-08"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02546-06"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800200200"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701478104"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3773(20020816)41:16<2937::AID-ANIE2937>3.0.CO;2-J"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.199323"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.145789"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05331-11"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.004416"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15613"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81430-0"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80066-5"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708109104"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161210790963751"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01339-10"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2013.12.022"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.11.4349-4359.2004"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.354126"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.390393"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00319-08"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-222547"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-11-40"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku183"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000498"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00373-15"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01060-08"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.067090"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzs051"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.12.10213-10217.1998"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2008.04.005"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807335105"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02496-08"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00649-09"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/v2051069"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12977-014-0086-8"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.16.10237-10246.2005"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2006.11.011"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20141"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01741-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.01741-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T14:00:45Z","timestamp":1646488845000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.01741-15"}},"subtitle":[],"editor":[{"given":"F.","family":"Kirchhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,12,15]]},"references-count":51,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2015,12,15]]}},"alternative-id":["10.1128\/JVI.01741-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.01741-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,15]]},"assertion":[{"value":"2015-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-09-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-11-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}