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Antimicrobial Agents and Chemotherapy, December 2009, p. 4987-4998, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00670-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

ADS-J1 Inhibits Human Immunodeficiency Virus Type 1 Entry by Interacting with the gp41 Pocket Region and Blocking Fusion-Active gp41 Core Formation{triangledown}

Hongtao Wang,1,{dagger} Zhi Qi,2,{dagger} Angi Guo,2 Qinchao Mao,1 Hong Lu,2 Xiuli An,2 Chenglai Xia,1 Xiaojuan Li,1 Asim K. Debnath,2 Shuguang Wu,1 Shuwen Liu,1* and Shibo Jiang1,2*

School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China,1 Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 100652

Received 16 May 2009/ Returned for modification 19 June 2009/ Accepted 18 September 2009

We previously identified a small-molecule anti-human immunodeficiency virus type 1 (anti-HIV-1) compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme-linked 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 a time-of-addition assay and an HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 does not block gp120-CD4 binding and exhibits a 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-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, using a surface plasmon resonance assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing the gp41 pocket region, resulting in the conformational 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.

* Corresponding author. Mailing address for S. Liu: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Phone: 86-20-61648538. Fax: 86-20-61648655. E-mail: liusw{at}smu.edu.cn. Mailing address for S. Jiang: Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065. Phone: (212) 570-3058. Fax: (212) 570-3099. E-mail: sjiang{at}nybloodcenter.org

{triangledown} Published ahead of print on 28 September 2009.

{dagger} These two authors made equal contributions.

Antimicrobial Agents and Chemotherapy, December 2009, p. 4987-4998, Vol. 53, No. 12
0066-4804/09/$08.00+0     doi:10.1128/AAC.00670-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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