Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)

Mashayekh, Siavash; Stunkard, Lee M.; Kienle, Maryline; Mathews, Irimpan I.; Khosla, Chaitan

doi:10.1021/acs.biochem.2c00451

Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)

Journal Article · Mon Oct 03 00:00:00 EDT 2022 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.2c00451· OSTI ID:1997986

Mashayekh, Siavash ^[1]; Stunkard, Lee M. ^[2]; Kienle, Maryline ^[2]; ^[3]; ^[2]

Stanford Univ., CA (United States); SLAC
Stanford Univ., CA (United States)
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1997986

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 21 Vol. 61; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)

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