Last update 01 Nov 2024

RT x HIV Ribonuclease H

Last update 01 Nov 2024

Basic Info

Related Targets

RTHIV Ribonuclease H

Drugs associated with RT x HIV Ribonuclease H

Benzisothiazolone Derivatives 1

Target

HIV Ribonuclease H x RT

Mechanism

HIV Ribonuclease H inhibitors [+1]

Active Org.

University of Pittsburgh School of Medicine

Originator Org.-

Active Indication

HIV Infections

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SP-1093V

Target

HIV Ribonuclease H x HIV-1 protease x RT

Mechanism

HIV Ribonuclease H inhibitors [+2]

Active Org.-

Originator Org.

McGill University

Active Indication-

Inactive Indication

HIV Infections

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with RT x HIV Ribonuclease H

100 Translational Medicine associated with RT x HIV Ribonuclease H

0 Patents (Medical) associated with RT x HIV Ribonuclease H

Literatures (Medical) associated with RT x HIV Ribonuclease H

01 Jun 2017·European Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

Q1 · MEDICINE

Article

Author: Wang, Zhengqiang ; Miller, Lena ; Vernekar, Sanjeev Kumar V ; Sarafianos, Stefan G ; Chen, Yue-Lei ; Tang, Jing ; Myshakina, Nataliya ; Huber, Andrew D ; Parniak, Michael A

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c.

26 May 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H

Q1 · MEDICINE

Article

Author: Wilson, Daniel J. ; Kirby, Karen A. ; Nagy, Eva ; Miller, Lena ; Parniak, Michael A. ; Liu, Feng ; Sarafianos, Stefan G. ; Wang, Zhengqiang ; Kankanala, Jayakanth

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.

24 Mar 2016·Journal of Medicinal ChemistryQ1 · MEDICINE

3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations

Q1 · MEDICINE

Article

Author: Miller, Lena ; Kirby, Karen A. ; Wilson, Daniel J. ; Wu, Bulan ; Tang, Jing ; Sarafianos, Stefan G. ; Wang, Zhengqiang ; Nagy, Eva ; Liu, Feng ; Parniak, Michael A.

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without significantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.

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