PL‐100, a novel HIV‐1 protease inhibitor displaying a high genetic barrier to resistance: An in vitro selection study

Abstract

The development of new HIV inhibitors with distinct resistance profiles is essential in order to combat the development of multi-resistant viral strains. A drug discovery program based on the identification of compounds that are active against drug-resistant viruses has produced PL-100, a novel potent protease inhibitor (PI) that incorporates a lysine-based scaffold. A selection for resistance against PL-100 in cord blood mononuclear cells was performed, using the laboratory-adapted IIIb strain of HIV-1, and it was shown that resistance appears to develop slower against this compound than against amprenavir, which was studied as a control. Four mutations in protease (PR) were selected after 25 weeks: two flap mutations (K45R and M46I) and two novel active site mutations (T80I and P81S). Site-directed mutagenesis revealed that all four mutations were required to develop low-level resistance to PL-100, which is indicative of the high genetic barrier of the compound. Importantly, these mutations did not cause cross-resistance to currently marketed PIs. In contrast, the P81S mutation alone caused hypersensitivity to two other PIs, saquinavir (SQV) and nelfinavir (NFV). Analysis of p55Gag processing showed that a marked defect in protease activity caused by mutation P81S could only be compensated when K45R and M46I were present. These data correlated well with the replication capacity (RC) of the mutant viruses as measured by a standard viral growth assay, since only viruses containing all four mutations approached the RC of wild type virus. X-ray crystallography provided insight on the structural basis of the resistance conferred by the identified mutations.

Structural basis for drug and substrate specificity exhibited by FIV encoding a chimeric FIV/HIV protease

“…5). Ser at this position also arose in HIV PR in response to the novel inhibitor PL-100 (Dandache et al, 2008). The orientation of Ser98 (or His98) in the P1 site implies that this residue could interact with Gag substrate.…”

Proteases and protease inhibitors in infectious diseases

“…PL‐100 contains a lysine‐based scaffold and forms hydrogen bonds with the flap of the HIV protease via the sulfonamide oxygens, displacing the connecting water molecule . This novel interaction gives the drug a high barrier to resistance and good activity against multidrug‐resistant HIV strains . The possibility of once daily dosing of the unboosted drug has also been reported as it was found to sufficiently inhibit CYP450 3A4/5 …”

“…190 This novel interaction gives the drug a high barrier to resistance and good activity against multidrug-resistant HIV strains. 191 The possibility of once daily dosing of the unboosted drug has also been reported as it was found to sufficiently inhibit CYP450 3A4/5. 166 The management of HIV/AIDS using protease inhibitors currently offers a good prognosis, however the side effects associated with these treatments are still a major concern.…”

Predictors of Failure on Second-line Antiretroviral Therapy with Protease Inhibitor Mutations in Uganda

“…Type of second-line ART with failure on second-line ART with PI mutations Patients who had "other" PIs like saquinavir and nel navir had higher odds of failure on secondline ART with PI mutations (p=0.029) compared to counterparts on Alluvia or Atazanavir. This could be associated with the higher pill burden of "other" PIs like saquinavir [37] and their low genetic barrier to resistance and reduced bioavailability [38]. We recommend to HIV clinical care specialists to give priority to prescribing PIs of higher genetic barrier resistance, and periodically review and assess patients on PIs such as saquinavir for resistance.…”