6UWC

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-08613

Summary for 6UWC

• Entry DOI: 10.2210/pdb6uwc/pdb
• Related: 4HLA 6D0D 6D0E
• Descriptor: Protease, (3aS,4S,7aR)-hexahydro-4H-furo[2,3-b]pyran-4-yl {(2S,3R)-1-(4-fluorophenyl)-3-hydroxy-4-[(2-methylpropyl)({2-[(propan-2-yl)amino]-1,3-benzothiazol-6-yl}sulfonyl)amino]butan-2-yl}carbamate (3 entities in total)
• Functional Keywords: protease inhibitors, aids, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22286.35

Authors

Yedidi, R.S.,Hayashi, H.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2019-11-05, release date: 2020-11-18, Last modification date: 2023-10-11)

Primary citation

Amano, M.,Yedidi, R.S.,Salcedo-Gomez, P.M.,Hayashi, H.,Hasegawa, K.,Martyr, C.D.,Ghosh, A.K.,Mitsuya, H.
Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease Inhibitors In Vitro.
Antimicrob.Agents Chemother., 66:e0171521-e0171521, 2022

PubMed Abstract: To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a P1-3,5--fluorophenyl or P1--monofluorophenyl ring and P2-tetrahydropyrano-tetrahydrofuran (-THF) with a sulfonamide isostere, are potent against wild-type HIV-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC]: 0.0001 to ∼0.0032 μM). As assessed with HIV-1 variants that had been selected to propagate at a 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly PI-resistant variants (EC: 0.003 to ∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activities against HIV-2 as well as severely multidrug-resistant clinical HIV-1 variants. Additionally, when we assessed with the blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS penetration among the evaluated compounds, including the majority of FDA-approved combination antiretroviral therapy (cART) drugs. In the crystallographic analysis of compound-PR complexes, it was demonstrated that the -THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen bond interactions with the active site of HIV-1 PR. Furthermore, both the P1-3,5--fluorophenyl- and P1--monofluorophenyl rings sustain greater contact surfaces and form stronger van der Waals interactions with PR than is the case with darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for patients infected with wild-type/multidrug-resistant HIV-1 strains and might serve as candidates for a preventive and/or therapeutic agent for HAND and other CNS complications.

PubMed: 34978889
DOI: 10.1128/AAC.01715-21

Experimental method

X-RAY DIFFRACTION (1.95 Å)