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

Abstract

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.

• Authors: Fei Yu, Lu Lu, Qi Liu, Xiaowen Yu, Lili Wang, Elaine He, Peng Zou, Lanying Du, Rogier W Sanders, Shuwen Liu, Shibo Jiang
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1838 Issue 5 Pg. 1296-305 (May 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24388952 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• HIV Envelope Protein gp41
• HIV Fusion Inhibitors
• Naphthalenesulfonates
• Peptides
• Triazines
• ADS J1

Topics

• Amino Acid Sequence
• HIV Envelope Protein gp41 (genetics, metabolism)
• HIV Fusion Inhibitors (pharmacology)
• HIV Infections (drug therapy, genetics, metabolism)
• HIV-1 (drug effects, genetics, metabolism)
• Humans
• Membrane Fusion (drug effects, genetics)
• Molecular Sequence Data
• Mutation
• Naphthalenesulfonates (pharmacology)
• Peptides (genetics, metabolism)
• Protein Structure, Tertiary
• Triazines (pharmacology)