Hepatitis B Virus Ribonuclease H: Mechanisms of Catalysis and Inhibition

reportActive / Technical Report | Accesssion Number: AD1208678 | Open PDF

Abstract:

The proposed project was a biochemical analyses of the hepatitis B virus (HBV) ribonuclease H(RNaseH). RNaseH activity is essential for HBV replication and is a target of drug discovery,but RNaseH enzymology is very poorly understood. RNaseH catalysis requires Mg++ ions. Aim 1 asked How do Mg++ ions and the heteroduplex substrate interact with the RNaseH? Aim 2 asked How do RNaseH inhibitors interact with the RNaseH? These studies were stymied by unanticipated difficulties producing recombinant HBV RNaseH, so we changed focus to conduct similar studies on human RNase H1 (huRH1). We found that huRH1 inhibitors are unusual noncompetitive inhibitors that bind to the active site. We propose a model in which, by binding to the active site, huRH1 inhibitors stabilize an inactive enzyme substrate inhibitor complex to block enzyme function. We also predicted and validated the structure of the HBV polymerase, of which the HBV RNaseH is one domain. This breakthrough structure has strong mechanistic implications and has already launched 3 new drug discovery projects against HBV.

Author(s):
Tavis, John
Author Organization(s):
SAINT LOUIS UNIV MO
Funding Organization(s):
ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND FORT DETRICK MD, FORT DETRICK, MD
Document Type:
Technical Report/Final Report
Publication Date:
2022 Nov 01
Pagination:
40

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DOCUMENT & CONTEXTUAL SUMMARY

Distribution Code:
A - Approved For Public Release
Distribution Statement: Public Release.
Copyright: Not Copyrighted

RECORD

Collection: TRECMS
Subject Terms
Descriptor(s):
chemistry, chemical synthesis, hepatitis, medical personnel, surface plasmon resonance, microbiology, molecular biology, proteins, amino acids, genetics, molecular dynamics, nucleic acids, viruses, viral structures, antiviral agents, crystal structure, data analysis
Keyword(s):
Hepatitis B virus, ribonuclease H, inhibitors, enzymology
Subject Categories:
Biological and Medical Sciences; Biological and Medical Sciences
Modernization Areas:
Fully Networked C3
Descriptor(s):
chemistry, chemical synthesis, hepatitis, amino acids, medical personnel, nucleic acids, proteins, surface plasmon resonance, kinetics, microbiology, molecular dynamics, molecules, acids, biomedical research, viruses, dissociation, dynamics
Creation Date:
2023 Sep 06
Update Date:
2023 Oct 02