5J1E

Crystal Structure of a Hydroxypyridone Carboxylic Acid Active-Site RNase H Inhibitor in Complex with HIV Reverse Transcriptase

Summary for 5J1E

• Entry DOI: 10.2210/pdb5j1e/pdb
• Descriptor: HIV-1 REVERSE TRANSCRIPTASE P66 DOMAIN, HIV-1 REVERSE TRANSCRIPTASE P51 DOMAIN, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); More
• Total number of polymer chains: 4
• Total formula weight: 228877.28

Authors

Kirby, K.A.,Sarafianos, S.G. (deposition date: 2016-03-29, release date: 2016-06-15, Last modification date: 2023-09-27)

Primary citation

Kankanala, J.,Kirby, K.A.,Liu, F.,Miller, L.,Nagy, E.,Wilson, D.J.,Parniak, M.A.,Sarafianos, S.G.,Wang, Z.
Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H.
J.Med.Chem., 59:5051-5062, 2016

PubMed Abstract: Targeting the clinically unvalidated reverse transcriptase (RT) associated ribonuclease H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biological evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochemical studies show that most analogues consistently inhibited HIV RT-associated RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. One compound showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallographic studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogues.

PubMed: 27094954
DOI: 10.1021/acs.jmedchem.6b00465

Experimental method

X-RAY DIFFRACTION (2.9 Å)