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Journal of Virology, October 2003, p. 10528-10536, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10528-10536.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Biochemical and Genetic Characterizations of a Novel Human Immunodeficiency Virus Type 1 Inhibitor That Blocks gp120-CD4 Interactions

Qi Guo,1 Hsu-Tso Ho,1 Ira Dicker,1 Li Fan,1 Nannan Zhou,1 Jacques Friborg,1 Tao Wang,2 Brian V. McAuliffe,1 Hwei-gene Heidi Wang,1 Ronald E. Rose,1 Hua Fang,1 Helen T. Scarnati,1 David R. Langley,3 Nicholas A. Meanwell,2 Ralph Abraham,4 Richard J. Colonno,1 and Pin-fang Lin1*

Department of Virology,1 Department of Chemistry,2 Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492,3 Department of Bioanalytical Science, Bristol-Myers Squibb Pharmaceutical Research Institute, Hopewell, New Jersey 085344

Received 24 April 2003/ Accepted 9 July 2003

BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.

* Corresponding author. Mailing address: Department of Virology, 5 Research Pkwy., Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492. Phone: (203) 677-6437. Fax: (203) 677-6088. E-mail: PinFang.Lin{at}bms.com.

Journal of Virology, October 2003, p. 10528-10536, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10528-10536.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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