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Antimicrobial Agents and Chemotherapy, December 2009, p. 5080-5087, Vol. 53, No. 12
0066-4804/09/$08.00+0 doi:10.1128/AAC.00759-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
New Small-Molecule Inhibitor Class Targeting Human Immunodeficiency Virus Type 1 Virion Maturation
Wade S. Blair,2,
Joan Cao,2
Juin Fok-Seang,1
Paul Griffin,1
Jason Isaacson,2
R. Lynn Jackson,2,
Edward Murray,1
Amy K. Patick,2,
Qinghai Peng,2
Manos Perros,1
Chris Pickford,1
Hua Wu,2 and
Scott L. Butler1*
Antiviral Biology, Pfizer Global Research & Development, Sandwich Laboratories, Sandwich, Kent, United Kingdom CT13 9NJ,1 Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 921212
Received 5 June 2009/ Returned for modification 9 July 2009/ Accepted 21 September 2009
A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.
* Corresponding author. Mailing address: Antiviral Biology, Pfizer Global Research & Development, Sandwich Laboratories, Sandwich, Kent, United Kingdom CT13 9NJ. Phone: 44 (0)1304 645282. Fax: 44 (0)1304 651819. E-mail: scott.butler{at}pfizer.com
Published ahead of print on 5 October 2009.
Present address: Biochemical Pharmacology Department, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080.
Present address: Nanogen Inc., 10398 Pacific Center Court, San Diego, CA 92121.
Present address: Adamas Pharmaceuticals, Inc., 1900 Powell St., Suite 1050, Emeryville, CA 94608.
Antimicrobial Agents and Chemotherapy, December 2009, p. 5080-5087, Vol. 53, No. 12
0066-4804/09/$08.00+0 doi:10.1128/AAC.00759-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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