Advanced piperazine-containing inhibitors target microbial β-glucuronidases linked to gut toxicity

Author:

Graboski Amanda L.1ORCID,Simpson Joshua B.2ORCID,Pellock Samuel J.2,Mehta Naimee3,Creekmore Benjamin C.2,Ariyarathna Yamuna3,Bhatt Aadra P.4,Jariwala Parth B.2,Sekela Josh J.2,Kowalewski Mark E.5,Barker Natalie K.6,Mordant Angie L.6,Borlandelli Valentina B.7,Overkleeft Hermen7ORCID,Herring Laura E.6,Jin Jian8ORCID,I. James Lindsey3,Redinbo Matthew R.25ORCID

Affiliation:

1. Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA

2. Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina, USA

3. Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA

4. Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

5. Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina, USA

6. UNC Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

7. Department of Bio-organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands

8. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Abstract

Leveraging medicinal chemistry and structural biology to optimize microbial GUS inhibitors to UNC10206581, which displays potent L1 and FMN GUS activity – the structural subclasses linked to GI toxicity via small molecule glucuronide reactivation.

Funder

National Institute of General Medical Sciences

Division of Graduate Education

Publisher

Royal Society of Chemistry (RSC)

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