PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing

Abstract

New HIV therapies are urgently needed to address the growing problem of drug resistance. In this article, we characterize the anti-HIV drug candidate 3-O-(3,3-dimethylsuccinyl) betulinic acid (PA-457). We show that PA-457 potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). We find that virions from PA-457-treated cultures are noninfectious and exhibit an aberrant particle morphology characterized by a spherical, acentric core and a crescent-shaped, electron-dense shell lying just inside the viral membrane. To identify the determinants of compound activity we selected for PA-457-resistant virus in vitro. Consistent with the effect on Gag processing, we found that mutations conferring resistance to PA-457 map to the p25 to p24 cleavage site. PA-457 represents a unique class of anti-HIV compounds termed maturation inhibitors that exploit a previously unidentified viral target, providing additional opportunities for HIV drug discovery.

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

“…The possible role of processing at the FIV CA-p1 cleavage junction in viral infectivity is currently under investigation. Interestingly, the processing of the equivalent HIV-1 CA-p2 junction, which is the final cleavage step in the temporal processing of HIV-1 Gag (26,46), is blocked by an experimental maturation inhibitor, PA-457 (bevirimat), resulting in the formation of aberrant, noninfectious HIV-1 (1,34).…”

The structural biology of HIV assembly

“…PA-457 does not bind free Gag, however, and therefore presumably recognizes SP1 in its assembled conformation. Cells treated with PA-457 release noninfectious virions with aberrant capsids that resemble those seen for viruses with mutations that inhibit CA-SP1 processing [115]. However, it appears that PA-457 does not completely block, but simply delays, proteolysis of the CA-SP1 junction [119], suggesting that Gag proteolysis and maturation must occur within a defined temporal window.…”

“…One class of maturation inhibitors is exemplified by 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (also called PA-457) [113,114], which inhibits HIV-1 replication in tissue culture and animal model systems, and is currently in Phase 2 clinical trials [115]. PA-457 inhibits Gag processing at the CA-SP1 junction and appears to bind directly to this site because the inhibitor is incorporated into assembling virions and because mutations at the CA-SP1 junction induce drug resistance [115][116][117][118]. PA-457 does not bind free Gag, however, and therefore presumably recognizes SP1 in its assembled conformation.…”

Update: Biological and Chemical Aspects of Senna spectabilis

“…31,61,62 Betulinic acid, isolated from leaves, fruits and flowers of Senna, is a highly bioactive triterpene, displaying anti-HIV, antibacterial, antimalarial and anti-inflammatory effects. 5,31,[63][64][65] Commonly known as 3β-hydroxy-lup-20-(29)-en-28-oic acid, this triterpene promises to be a potential drug for cancer treatment due to its cytotoxicity against various cancer cell lines (lung, ovarian, neuroand glioblastoma and head/neck carcinomas), selective inhibition of human melanoma, apoptosis induction in human neurobastoma and low toxicity to healthy cells. 66 Ursolic acid, found either free or bounded to saponins, is a common constituent of fruits from human diet such as apple, guava and blueberry.…”