5V4Y

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-09510

Summary for 5V4Y

• Entry DOI: 10.2210/pdb5v4y/pdb
• Descriptor: Protease, (3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate (3 entities in total)
• Functional Keywords: grl-09510, hiv-1 protease, protease-inhibitor, pyran, furan, nonpeptidic, hydrolase-hydrolase inhibitor complex, crown-thf, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 11314.31

Authors

Yedidi, R.S.,Delino, N.S.,Das, D.,Kaufman, J.D.,Wingfield, P.T.,Ghosh, A.K.,Mitsuya, H. (deposition date: 2017-03-11, release date: 2017-09-13, Last modification date: 2023-10-04)

Primary citation

Amano, M.,Miguel Salcedo-Gomez, P.,Yedidi, R.S.,Delino, N.S.,Nakata, H.,Venkateswara Rao, K.,Ghosh, A.K.,Mitsuya, H.
GRL-09510, a Unique P2-Crown-Tetrahydrofuranylurethane -Containing HIV-1 Protease Inhibitor, Maintains Its Favorable Antiviral Activity against Highly-Drug-Resistant HIV-1 Variants in vitro.
Sci Rep, 7:12235-12235, 2017

PubMed Abstract: We report that GRL-09510, a novel HIV-1 protease inhibitor (PI) containing a newly-generated P2-crown-tetrahydrofuranylurethane (Crwn-THF), a P2'-methoxybenzene, and a sulfonamide isostere, is highly active against laboratory and primary clinical HIV-1 isolates (EC: 0.0014-0.0028 μM) with minimal cytotoxicity (CC: 39.0 μM). Similarly, GRL-09510 efficiently blocked the replication of HIV-1 variants, which were capable of propagating at high-concentrations of atazanavir, lopinavir, and amprenavir (APV). GRL-09510 was also potent against multi-drug-resistant clinical HIV-1 variants and HIV-2. Under the selection condition, where HIV-1 rapidly acquired significant resistance to APV, an integrase inhibitor raltegravir, and a GRL-09510 congener (GRL-09610), no variants highly resistant against GRL-09510 emerged over long-term in vitro passage of the virus. Crystallographic analysis demonstrated that the Crwn-THF moiety of GRL-09510 forms strong hydrogen-bond-interactions with HIV-1 protease (PR) active-site amino acids and is bulkier with a larger contact surface, making greater van der Waals contacts with PR than the bis-THF moiety of darunavir. The present data demonstrate that GRL-09510 has favorable features for treating patients infected with wild-type and/or multi-drug-resistant HIV-1 variants, that the newly generated P2-Crwn-THF moiety confers highly desirable anti-HIV-1 potency. The use of the novel Crwn-THF moiety sheds lights in the design of novel PIs.

PubMed: 28947797
DOI: 10.1038/s41598-017-12052-9

Experimental method

X-RAY DIFFRACTION (1.9 Å)