ADS-J1 inhibits HIV-1 infection and membrane fusion by targeting the highly conserved pocket in the gp41 NHR-trimer

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• 作者：Fei Yu^a ; ^b ; ^c ; Lu Lu^b ; Qi Liu^b ; Xiaowen Yu^c ; Lili Wang^c ; Elaine He^c ; Peng Zou^c ; Lanying Du^c ; Rogier W. Sanders^d ; ^e ; Shuwen Liu^a ; ^{liusw@smu.edu.cn" class="auth_mail} ; Shibo Jiang^a ; ^b ; ^c ; ^{shibojiang@fudan.edu.cn" class="auth_mail}
• 关键词：CD ; Circular Dichroism ; CHR ; C-terminal heptad repeat ; Env ; envelope protein ; Fd ; foldon ; HIV-1 ; human immunodeficiency virus 1 ; IC50 ; concentration causing 50% inhibition ; NHR ; N-terminal heptad repeat ; N-PAGE ; native polyacrylamide gel electrophoresis ; PBD ; pocket-binding domain ; 6-HB ; six-helix bundle
• 刊名：Biochimica et Biophysica Acta (BBA)/Biomembranes
• 出版年：May, 2014
• 年：2014
• 卷：1838
• 期：5
• 页码：1296-1305
• 全文大小：859 K

文摘

We previously identified a potent small-molecule human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, termed ADS-J1, and hypothesized that it mainly targeted the hydrophobic pocket in the gp41 N-terminal heptad repeat (NHR) trimer. However, this hypothesis has been challenged by the fact that ADS-J1 cannot induce drug-resistance mutation in the gp41 pocket region. Therefore, we show herein that HIV-1 mutants resistant to T2635, a peptide derived from the gp41 C-terminal heptad repeat (CHR) region with pocket-binding domain (PBD), were also resistant to ADS-J1. We also show that pseudoviruses with mutations at positions 64 and 67 in the gp41 pocket region were highly resistant to ADS-J1 and C34, another CHR-peptide with PBD, but relatively sensitive to T20, a CHR-peptide without PBD. ADS-J1 could effectively bind to N36Fd, a mimic of the gp41 NHR-trimer with pocket exposed, and block binding of C34 to N36Fd trimer to form six-helix bundle (6-HB). However, ADS-J1 was less effective in binding to N36Fd trimer with mutations in the gp41 pocket region, such as N36(Q64A)Fd, N36(Q64L)Fd, N36(A67G)Fd, N36(A67S)Fd, and N36(Q66R)Fd, as well as less effective in blocking 6-HB formation between C34 and these mutant N36Fd trimers. These results confirm that ADS-J1 mainly targets the pocket region in the HIV-1 gp41 NHR trimer and suggest that it could be used as a lead for developing small-molecule HIV fusion inhibitors and as a molecule probe for studying the mechanisms of gp41-mediated membrane fusion.