ADS-J1 inhibits HIV-1 entry by interacting with the gp41 pocket region and blocking the fusion-active gp41 core formation. - Related Articles
ADS-J1 inhibits HIV-1 entry by interacting with the gp41 pocket region and blocking the fusion-active gp41 core formation.
Antimicrob Agents Chemother. 2009 Sep 28;
Authors: Wang H, Qi Z, Guo A, Mao Q, Lu H, An X, Xia C, Li X, Debnath AK, Wu S, Liu S, Jiang S
We previously identified a small molecule anti-HIV-1 compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme immunosorbent assay (ELISA) as a secondary screening method. In the present study, we demonstrated that ADS-J1 is an HIV-1 entry inhibitor as determined by time-of-addition assay and HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 did not block gp120-CD4 binding and exhibited marginal interaction with the HIV-1 coreceptor CXCR4. However, ADS-J1 inhibited the fusion-active gp41 core formation mimicked by peptides derived from the viral gp41 N- and C-terminal heptad repeats (NHR and CHR) as determined by ELISA, native-polyacrylamide gel electrophoresis and circular dichroism (CD). Moreover, using surface plasmon resonance (SPR) assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing gp41 pocket region, resulting in the conformation change of IQN17 and the blockage of its interaction with a short D-peptide, PIE7. The positively charged residue (K574) located in the gp41 pocket region is critical for the binding of ADS-J1 to NHR. These results suggest that ADS-J1 may bind to the viral gp41 NHR region through its hydrophobic and ionic interactions with the hydrophobic and positively charged resides located in the pocket region, subsequently blocking the association between the gp41 NHR and CHR regions to form the fusion-active gp41 core, thereby inhibiting HIV-1 mediated membrane fusion and virus entry.
PMID: 19786602 [PubMed - as supplied by publisher] [PubMed-HIV]