New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
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.
Blair
Wade S
WS
Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 921212, USA.
Cao
Joan
J
Fok-Seang
Juin
J
Griffin
Paul
P
Isaacson
Jason
J
Jackson
R Lynn
RL
Murray
Edward
E
Patick
Amy K
AK
Peng
Qinghai
Q
Perros
Manos
M
Pickford
Chris
C
Wu
Hua
H
Butler
Scott L
SL
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D036022:Capsid Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D014771:Virion / Q000187:drug effects* / Q000378:metabolism*
D019380:Anti-HIV Agents; D036022:Capsid Proteins