Determinants of activity of the HIV-1 maturation inhibitor PA-457.
3-O-(3',3'-dimethylsuccinyl) betulinic acid, also termed PA-457 or DSB, is a novel HIV-1 inhibitor that blocks virus maturation by disrupting cleavage of the capsid precursor, CA-SP1. To better define the molecular target for PA-457, we prepared a panel of mutant viruses with point deletions spanning the CA-SP1 cleavage domain and characterized each of these viruses for PA-457 sensitivity. Our results indicate that amino acid residues in the N-terminal half of SP1 serve as determinants of PA-457 activity, while residues in the C-terminal half of SP1 were not involved in compound activity. These findings support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage and identify the CA-SP1 domain as the primary viral determinant for this novel inhibitor of HIV-1 replication.
Li
Feng
F
Panacos Pharmaceuticals, 209 Perry Parkway, Gaithersburg, MD 20877, USA.
Zoumplis
Dorian
D
Matallana
Claudia
C
Kilgore
Nicole R
NR
Reddick
Mary
M
Yunus
Abdul S
AS
Adamson
Catherine S
CS
Salzwedel
Karl
K
Martin
David E
DE
Allaway
Graham P
GP
Freed
Eric O
EO
Wild
Carl T
CT
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008826:Microbial Sensitivity Tests / Q000379:methods; D017354:Point Mutation; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013386:Succinates / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D015683:Gene Products, gag; D011498:Protein Precursors; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes