Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)
Abstract
Pyrimidine nucleotide biosynthesis in humans is a promising chemotherapeutic target for infectious diseases caused by RNA viruses. Because mammalian cells derive pyrimidine ribonucleotides through a combination of de novo biosynthesis and salvage, combined inhibition of dihydroorotate dehydrogenase (DHODH; the first committed step in de novo pyrimidine nucleotide biosynthesis) and uridine/cytidine kinase 2 (UCK2; the first step in salvage of exogenous nucleosides) strongly attenuates viral replication in infected cells. However, while several pharmacologically promising inhibitors of human DHODH are known, to date there are no reports of medicinally viable leads against UCK2. Here we use structure-based drug prototyping to identify two classes of promising leads that non-competitively inhibit UCK2 activity. In the process we have identified a hitherto unknown allosteric site at the inter-subunit interface of this homotetrameric enzyme. By reducing the kcat of human UCK2 without altering its KM, these new inhibitors have the potential to enable systematic dialing of the fractional inhibition of pyrimidine salvage to achieve the desired antiviral effect with minimal host toxicity.
- Authors:
-
[2];
[1]
- Stanford Univ., CA (United States)
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- OSTI Identifier:
- 1997986
- Grant/Contract Number:
- AC02-76SF00515; 1U19-AI109662
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Biochemistry
- Additional Journal Information:
- Journal Volume: 61; Journal Issue: 21; Journal ID: ISSN 0006-2960
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; genetics; inhibition; inhibitors
Citation Formats
Mashayekh, Siavash, Stunkard, Lee M., Kienle, Maryline, Mathews, Irimpan I., and Khosla, Chaitan. Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2). United States: N. p., 2022.
Web. doi:10.1021/acs.biochem.2c00451.
Mashayekh, Siavash, Stunkard, Lee M., Kienle, Maryline, Mathews, Irimpan I., & Khosla, Chaitan. Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2). United States. https://doi.org/10.1021/acs.biochem.2c00451
Mashayekh, Siavash, Stunkard, Lee M., Kienle, Maryline, Mathews, Irimpan I., and Khosla, Chaitan. Mon .
"Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)". United States. https://doi.org/10.1021/acs.biochem.2c00451. https://www.osti.gov/servlets/purl/1997986.
@article{osti_1997986,
title = {Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)},
author = {Mashayekh, Siavash and Stunkard, Lee M. and Kienle, Maryline and Mathews, Irimpan I. and Khosla, Chaitan},
abstractNote = {Pyrimidine nucleotide biosynthesis in humans is a promising chemotherapeutic target for infectious diseases caused by RNA viruses. Because mammalian cells derive pyrimidine ribonucleotides through a combination of de novo biosynthesis and salvage, combined inhibition of dihydroorotate dehydrogenase (DHODH; the first committed step in de novo pyrimidine nucleotide biosynthesis) and uridine/cytidine kinase 2 (UCK2; the first step in salvage of exogenous nucleosides) strongly attenuates viral replication in infected cells. However, while several pharmacologically promising inhibitors of human DHODH are known, to date there are no reports of medicinally viable leads against UCK2. Here we use structure-based drug prototyping to identify two classes of promising leads that non-competitively inhibit UCK2 activity. In the process we have identified a hitherto unknown allosteric site at the inter-subunit interface of this homotetrameric enzyme. By reducing the kcat of human UCK2 without altering its KM, these new inhibitors have the potential to enable systematic dialing of the fractional inhibition of pyrimidine salvage to achieve the desired antiviral effect with minimal host toxicity.},
doi = {10.1021/acs.biochem.2c00451},
journal = {Biochemistry},
number = 21,
volume = 61,
place = {United States},
year = {Mon Oct 03 00:00:00 EDT 2022},
month = {Mon Oct 03 00:00:00 EDT 2022}
}
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