8U69

Crystal Structure of HIV-1 Reverse Transcriptase in Complex with 3-chloro-5-(4-chloro-2-(2-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)benzonitrile (JLJ334), a non-nucleoside inhibitor

Summary for 8U69

• Entry DOI: 10.2210/pdb8u69/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, 3-chloro-5-{4-chloro-2-[2-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}benzonitrile, ... (4 entities in total)
• Functional Keywords: reverse transcriptase, antiviral, drug design, hiv-1, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 2
• Total formula weight: 114481.40

Authors

Hollander, K.,Carter, Z.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2023-09-13, release date: 2023-11-08)

Primary citation

Prucha, G.R.,Henry, S.,Hollander, K.,Carter, Z.J.,Spasov, K.A.,Jorgensen, W.L.,Anderson, K.S.
Covalent and noncovalent strategies for targeting Lys102 in HIV-1 reverse transcriptase.
Eur.J.Med.Chem., 262:115894-115894, 2023

PubMed Abstract: Reverse transcriptase (RT) is one of three key proteins responsible for the replication cycle of HIV-1 in the host. Several classes of inhibitors have been developed to target the enzyme, with non-nucleoside reverse transcriptase inhibitors forming first-line treatment. Previously, covalent RT inhibitors have been identified and found to bind irreversibly to commonly mutated residues such as Y181C. In this work we aim to circumvent the issue of NNRTI resistance through targeting K102, which has not yet been identified to confer drug resistance. As reported here, 34 compounds were synthesized and characterized biochemically and structurally with wild-type (WT) HIV-1 RT. Two of these inhibitors demonstrate covalent inhibition as evidenced by protein crystallography, enzyme kinetics, mass spectrometry, and antiviral potency in HIV-1 infected human T-cell assays.

PubMed: 37883896
DOI: 10.1016/j.ejmech.2023.115894

Experimental method

X-RAY DIFFRACTION (2.45 Å)