6d0e | pdb_00006d0e
X-ray crystal structure of wild type HIV-1 protease in complex with GRL-084-13
Structural highlights
Publication Abstract from PubMedPresently, no specific therapeutics for the HIV-1-related central nervous system (CNS) complications exists. Here we report that three newly-designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, -084-13, and -087-13, which contain P1-3,5-bis-fluorophenyl- or P1-para-monofluorophenyl-ring, and P2-bis-tetrahydrofuran (bis-THF) or P2-tetrahydropyrano-tetrahydrofuran (Tp-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1s and primary clinical isolates (EC50: 0.0002 approximately 0.003 muM) with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC50: 0.002 approximately 0.047 muM) that had been selected to propagate at high-concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2ROD as well as multi-drug-resistant clinical HIV-1 variants isolated from AIDS patients, who no longer responded to existing antiviral regimens after long-term therapy. Long-term drug-selection experiments revealed that the emergence of resistant-HIV-1 against these CNS-targeting PIs was substantially delayed. In addition, the CNS-targeting PIs showed the most favorable CNS-penetration properties among the tested compounds including various FDA-approved anti-HIV-1 drugs, as assessed with the in vitro blood-brain barrier reconstruction system. Crystallographic analysis demonstrated that the bicyclic rings at the P2 moiety of the CNS-targeting PIs form strong hydrogen-bond interactions with HIV-1 protease (PR) active-site. Moreover, both the P1-3,5-bis-fluorophenyl- and P1-para-monofluorophenyl-rings sustain greater contact surfaces and form greater van der Waals contacts with PR than in the case of darunavir (DRV). The data suggest that the present CNS-targeting PIs have desirable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1s, and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications. Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications.,Amano M, Salcedo-Gomez PM, Yedidi RS, Zhao R, Hayashi H, Hasegawa K, Nakamura T, Martyr CD, Ghosh AK, Mitsuya H Antimicrob Agents Chemother. 2019 May 6. pii: AAC.00466-19. doi:, 10.1128/AAC.00466-19. PMID:31061155[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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