6D0D

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-087-13

Summary for 6D0D

• Entry DOI: 10.2210/pdb6d0d/pdb
• Descriptor: Protease, (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-yl [(2S,3R)-1-(4-fluorophenyl)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}butan-2-yl]carbamate (3 entities in total)
• Functional Keywords: hiv-1 protease, protease inhibitor, darunavir, fluorophenyl, nonpeptidic, tmc-126, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22202.20

Authors

Yedidi, R.S.,Hayashi, H.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2018-04-10, release date: 2019-05-01, Last modification date: 2023-10-04)

Primary citation

Amano, M.,Salcedo-Gomez, P.M.,Yedidi, R.S.,Zhao, R.,Hayashi, H.,Hasegawa, K.,Nakamura, T.,Martyr, C.D.,Ghosh, A.K.,Mitsuya, H.
Novel Central Nervous System (CNS)-Targeting Protease Inhibitors for Drug-Resistant HIV Infection and HIV-Associated CNS Complications.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: There is currently no specific therapeutics for the HIV-1-related central nervous system (CNS) complications. Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5--fluorophenyl or P1--monofluorophenyl ring, and P2--tetrahydrofuran (-THF) or P2-tetrahydropyrano-tetrahydrofuran (-THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC], 0.0002 to ∼0.003 μM), with minimal cytotoxicity. These CNS-targeting PIs efficiently suppressed the replication of HIV-1 variants (EC, 0.002 to ∼0.047 μM) that had been selected to propagate at high concentrations of conventional HIV-1 PIs. Such CNS-targeting PIs maintained their antiviral activity against HIV-2 as well as multidrug-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 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--fluorophenyl and P1--monofluorophenyl rings sustain 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 multidrug-resistant HIV-1 strains and might serve as promising preventive and/or therapeutic candidates for HIV-1-associated neurocognitive disorders (HAND) and other CNS complications.

PubMed: 31061155
DOI: 10.1128/AAC.00466-19

Experimental method

X-RAY DIFFRACTION (1.85 Å)