8FCE

HIV-1 Reverse Transcriptase in complex with 7-membered bicyclic core NNRTI

Summary for 8FCE

• Entry DOI: 10.2210/pdb8fce/pdb
• Descriptor: p66 RT, p51 RT, 4-[(9-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]benzonitrile, ... (5 entities in total)
• Functional Keywords: hiv-1, reverse transcriptase, inhibitor, antiviral, viral protein
• Biological source: HIV whole-genome vector AA1305#18; More
• Total number of polymer chains: 2
• Total formula weight: 116547.56

Authors

Lansdon, E.B. (deposition date: 2022-12-01, release date: 2023-02-01, Last modification date: 2024-05-22)

Primary citation

Prener, L.,Baszczynski, O.,Kaiser, M.M.,Dracinsky, M.,Stepan, G.,Lee, Y.J.,Brumshtein, B.,Yu, H.,Jansa, P.,Lansdon, E.B.,Janeba, Z.
Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.
J.Med.Chem., 66:1761-1777, 2023

PubMed Abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds , , and carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7×). Most importantly, compound exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds , , and to the reverse transcriptase were studied by X-ray crystallography.

PubMed: 36652602
DOI: 10.1021/acs.jmedchem.2c01574

Experimental method

X-RAY DIFFRACTION (2.77 Å)