Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2

Xue, Yiying; Mei, Husheng; Chen, Yisa; Griffin, James D.; Liu, Qingsong; Weisberg, Ellen; Yang, Jing

doi:10.1002/mco2.254

Cited by 2 publications

(1 citation statement)

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“…Various known drugs are currently in the research spotlight for the possibility of being repurposed for COVID-19 treatment. − A noteworthy class of compounds that are currently being widely studied as potential SARS-CoV-2 suppressors is the derivatives of 3-hydroxypyrazine-2-carboxamide, known as compound T-1105 (Chart , compound 1a). These compounds were developed by Toyama Chemical Co., Ltd., for influenza treatment and have later been shown as potent inhibitors against nonrelated infections such as Ebola, rabies, yellow fewer, and many others. − The most notorious and researched derivative is the compound T-705 (6-fluoro-3-hydroxypyrazine-2-carboxamide, compound 1b), currently used against COVID-19 in various countries and widely known as “favipiravir”.…”

Section: Introductionmentioning

confidence: 99%

Designing an Efficient Biocatalyst for the Phosphoribosylation of Antiviral Pyrazine-2-carboxamide Derivatives

Zayats,

Fateev,

Abramchik

et al. 2024

ACS Catal.

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The development of technologies for the efficient synthesis of innovative antiviral compounds remains an important challenge for modern biotechnology, especially in the context of the recent COVID-19 pandemic. One of the drugs that is currently in the research spotlight for potential anti-SARS-CoV-2 activity is the purine mimetic prodrug compound T-705, also known as favipiravir. Along with a similar compound, T-1105, the activation of T-705 is limited by the low rate of phosphoribosylation, mediated by an enzyme named hypoxanthineguanine phosphoribosyltransferase (HGPRT). Therefore, the synthesis of phosphoribosylated/ribosylated derivatives of these prodrugs is a viable direction for the discovery and development of antiviral pharmaceuticals. However, the chemical synthesis of such compounds is a complex and laborious process, whereas enzymatic cascades are not feasible because of the narrow HGPRT substrate specificity. Here, we report the successful rational design of an efficient biocatalyst for T-705/T-1105 phosphoribosylation. With two rounds of Thermus thermophilus HB27 HGPRT active site optimization, we have achieved a 325-fold increase in k cat toward the compound T-705 and a 125-fold increase toward T-1105 accompanied by a multifold decrease in K M . The practical applicability of the designed mutant was illustrated through the preparative synthesis of T-705/T-1105 nucleotide derivatives. Our engineered biocatalyst can become a basis for the technologies of enzymatic and chemoenzymatic synthesis of various T-705/T-1105 derivatives with proven antiviral activity. Moreover, our results provide insight into the molecular mechanism of T-705/T-1105 phosphoribosylation, including the experimental evidence explaining the reasons behind the low activity of HGPRT toward these compounds.

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