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Antimicrobial Agents and Chemotherapy, November 2004, p. 4349-4359, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4349-4359.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion

Shibo Jiang,* Hong Lu, Shuwen Liu, Qian Zhao, Yuxian He, and Asim K. Debnath

Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York

Received 14 April 2004/ Returned for modification 28 May 2004/ Accepted 13 July 2004

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of "drug-like" compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the {alpha}-helical conformation. They blocked a D-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.

* Corresponding author. Mailing address: Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th St., New York, NY 10021. Phone: (212) 570-3058. Fax: (212) 570-3099. E-mail: sjiang{at}nybloodcenter.org.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4349-4359, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4349-4359.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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