更新于：2024-11-01

HIV核糖核酸酶H

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 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

Ribonuclease H function inhibitor(Université De Lille)

靶点

HIV核糖核酸酶H x HIV integrase

作用机制

HIV核糖核酸酶H抑制剂 [+1]

在研机构

Université De Lille

原研机构

Université De Lille

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 HIV核糖核酸酶H 相关的临床结果

登录后查看更多信息

100 项与 HIV核糖核酸酶H 相关的转化医学

登录后查看更多信息

0 项与 HIV核糖核酸酶H 相关的专利（医药）

登录后查看更多信息

项与 HIV核糖核酸酶H 相关的文献（医药）

2023-10-26·Journal of medicinal chemistry1区 · 医学

Inhibiting HCMV pUL89-C Endonuclease with Metal-Binding Compounds.

1区 · 医学

Review

作者: Geraghty, Robert J ; Wang, Zhengqiang ; Jagtap, Ajit Dhananjay

Human cytomegalovirus (HCMV) infects individuals of all ages and establishes a lifelong latency. Current antiviral drugs are suboptimal in efficacy and safety and ineffective against resistant/refractory HCMV. Therefore, there is an unmet clinical need for efficacious, safe, and mechanistically novel HCMV drugs. The recent Food and Drug Administration (FDA) approval of letermovir (LTV) validated the HCMV terminase complex as a new target for antiviral development. LTV targets terminase subunit pUL56 but not the main endonuclease enzymatic function housed in the C terminus of subunit pUL89 (pUL89-C). Structurally and mechanistically, pUL89-C is an RNase H-like viral endonuclease entailing two divalent metal ions at the active site. In recent years, numerous studies have extensively explored pUL89-C inhibition using metal-chelating chemotypes, an approach previously used for inhibiting HIV ribonuclease H (RNase H) and integrase strand transfer (INST). Collectively, the work summarized herein validates the use of metal-binding scaffolds for designing potent and specific pUL89-C inhibitors.

2023-07-13·Viruses

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication.

Article

作者: Kwak, Mi-Jeong ; Asthana, Abhishek ; Tramontano, Enzo ; Corona, Angela ; Jung, Jae U ; Gaughan, Christina ; Jha, Babal Kant ; Shin, Woo-Jin ; Schobert, Rainer ; Biersack, Bernhard ; Silverman, Robert H

Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3'-to-5' exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

2023-06-09·Nucleic Acids Research

Controlled sulfur-based engineering confers mouldability to phosphorothioate antisense oligonucleotides

Article

作者: Genna, Vito ; Brun-Heath, Isabelle ; Iglesias-Fernández, Javier ; González, Carlos ; Villalobos, Anabella ; Reyes-Fraile, Laura ; Wan, Brad ; Orozco, Modesto ; Terrazas, Montserrat ; Sciabola, Simone ; Guckian, Kevin ; Villegas, Nuria ; Seth, Punit ; Cabrero, Cristina

AbstractPhosphorothioates (PS) have proven their effectiveness in the area of therapeutic oligonucleotides with applications spanning from cancer treatment to neurodegenerative disorders. Initially, PS substitution was introduced for the antisense oligonucleotides (PS ASOs) because it confers an increased nuclease resistance meanwhile ameliorates cellular uptake and in-vivo bioavailability. Thus, PS oligonucleotides have been elevated to a fundamental asset in the realm of gene silencing therapeutic methodologies. But, despite their wide use, little is known on the possibly different structural changes PS-substitutions may provoke in DNA·RNA hybrids. Additionally, scarce information and significant controversy exists on the role of phosphorothioate chirality in modulating PS properties. Here, through comprehensive computational investigations and experimental measurements, we shed light on the impact of PS chirality in DNA-based antisense oligonucleotides; how the different phosphorothioate diastereomers impact DNA topology, stability and flexibility to ultimately disclose pro-Sp S and pro-Rp S roles at the catalytic core of DNA Exonuclease and Human Ribonuclease H; two major obstacles in ASOs-based therapies. Altogether, our results provide full-atom and mechanistic insights on the structural aberrations PS-substitutions provoke and explain the origin of nuclease resistance PS-linkages confer to DNA·RNA hybrids; crucial information to improve current ASOs-based therapies.