更新于：2024-11-01

RT x HIV核糖核酸酶H

更新于：2024-11-01

基本信息

关联

项与 RT x HIV核糖核酸酶H 相关的药物

Benzisothiazolone Derivatives 1

靶点

HIV核糖核酸酶H x RT

作用机制

HIV核糖核酸酶H抑制剂 [+1]

在研机构

University of Pittsburgh School of Medicine

原研机构-

在研适应症

HIV感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

SP-1093V

靶点

HIV核糖核酸酶H x HIV-1 protease x RT

作用机制

HIV核糖核酸酶H抑制剂 [+2]

在研机构-

原研机构

McGill University

在研适应症-

非在研适应症

HIV感染

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RT x HIV核糖核酸酶H 相关的临床结果

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100 项与 RT x HIV核糖核酸酶H 相关的转化医学

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0 项与 RT x HIV核糖核酸酶H 相关的专利（医药）

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项与 RT x HIV核糖核酸酶H 相关的文献（医药）

2017-06-01·European Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: 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.

2016-05-26·Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: 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.

2016-03-24·Journal of Medicinal Chemistry1区 · 医学

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

1区 · 医学

Article

作者: 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.