Exploring Viral RNA Methyltransferases for Antiviral Drug Design

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00604155" target="_blank" >RIV/61388963:_____/24:00604155 - isvavai.cz</a>

Výsledek na webu

—

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Exploring Viral RNA Methyltransferases for Antiviral Drug Design

Popis výsledku v původním jazyce

Our investigation deals with viral RNA methyltransferases, pivotal enzymes responsible for methylating the 5’ cap structure of viral RNA. Specifically, these methyltransferases target cap GTP at position 7 and the first nucleotide at position 2’. Our focus centers on methyltransferases from various viruses, with particular attention to two enzymes—nsp14 and nsp16/nsp10—from the SARS-CoV-2 virus. Our primary goal involves obtaining crystal structures of these enzymes to facilitate the design of inhibitors for crucial SARS-CoV-2 enzymes. Leveraging the structural model, we developed initial nanomolar inhibitors for the SARS-CoV-2 nsp14 N-7 methyltransferase, subsequently refining them through rational design. Recent successes include obtaining the crystal structure of an optimized inhibitor derivative in a complex with the nsp14 methyltransferase domain. Additionally, our team achieved a milestone by securing the first crystal structure of the nsp16/nsp10 complex with a non-selective pan-methyltransferase inhibitor. Further exploration revealed an allosteric cryptic cavity in nsp16/nsp10 capable of binding both covalent and non-covalent inhibitors. Shifting our focus to the monkeypox virus, we obtained the crystal structure of its 2’-O methyltransferase (VP39 protein), established an HTS assay, and screened a library of approximately 500 SAH derivatives. This effort led to the identification of several potent inhibitors for the VP39 methyltransferase, offering potential avenues for antiviral drug development.

Název v anglickém jazyce

Exploring Viral RNA Methyltransferases for Antiviral Drug Design

Popis výsledku anglicky

Our investigation deals with viral RNA methyltransferases, pivotal enzymes responsible for methylating the 5’ cap structure of viral RNA. Specifically, these methyltransferases target cap GTP at position 7 and the first nucleotide at position 2’. Our focus centers on methyltransferases from various viruses, with particular attention to two enzymes—nsp14 and nsp16/nsp10—from the SARS-CoV-2 virus. Our primary goal involves obtaining crystal structures of these enzymes to facilitate the design of inhibitors for crucial SARS-CoV-2 enzymes. Leveraging the structural model, we developed initial nanomolar inhibitors for the SARS-CoV-2 nsp14 N-7 methyltransferase, subsequently refining them through rational design. Recent successes include obtaining the crystal structure of an optimized inhibitor derivative in a complex with the nsp14 methyltransferase domain. Additionally, our team achieved a milestone by securing the first crystal structure of the nsp16/nsp10 complex with a non-selective pan-methyltransferase inhibitor. Further exploration revealed an allosteric cryptic cavity in nsp16/nsp10 capable of binding both covalent and non-covalent inhibitors. Shifting our focus to the monkeypox virus, we obtained the crystal structure of its 2’-O methyltransferase (VP39 protein), established an HTS assay, and screened a library of approximately 500 SAH derivatives. This effort led to the identification of several potent inhibitors for the VP39 methyltransferase, offering potential avenues for antiviral drug development.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů