Unusual Binding Mode of an HIV-1 Protease Inhibitor Explains its Potency against Multi-drug-resistant Virus Strains

摘要: Abstract Protease inhibitors (PIs) are an important class of drugs for the treatment HIV infection. However, in course treatment, resistant viral variants with reduced sensitivity to PIs often emerge and become a major obstacle successful control load. On basis compound equipotently inhibiting HIV-1 2 proteases (PR), we have designed pseudopeptide inhibitor, QF34, that efficiently inhibits wide variety PR variants. In order analyze potency constructed species harboring typical (signature) mutations confer resistance commercially available PIs. Kinetic analyses showed these mutated PRs were inhibited up 1000-fold less by clinically approved contrast, all effectively QF34. clinical study, monitored 30 HIV-positive patients Czech Republic undergoing highly active antiretroviral therapy, identified PI revealed QF34 retained its subnanomolar against multi-drug X-ray crystallographic analysis molecular modeling experiments explained specificity QF34: this inhibitor binds unusual manner, thus avoiding contact sites upon development, binding mode consequently energy is therefore preserved complex variant. These results suggest promising route design second-generation