Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering

Christopher T. Saeui, Lingshu Liu, Esteban Urias, Justin Morrissette-Mcalmon, Rahul Bhattacharya, Kevin J Yarema

Research output: Contribution to journalArticle

Abstract

In this study, we catalog structure activity relationships (SAR) of several short chain fatty acid (SCFA)-modified hexosamine analogues used in metabolic glycoengineering (MGE) by comparing in silico and experimental measurements of physiochemical properties important in drug design. We then describe the impact of these compounds on selected biological parameters that influence the pharmacological properties and safety of drug candidates by monitoring P-glycoprotein (Pgp) efflux, inhibition of cytochrome P450 3A4 (CYP3A4), hERG channel inhibition, and cardiomyocyte cytotoxicity. These parameters are influenced by length of the SCFAs (e.g., acetate vs n-butyrate), which are added to MGE analogues to increase the efficiency of cellular uptake, the regioisomeric arrangement of the SCFAs on the core sugar, the structure of the core sugar itself, and by the type of N-acyl modification (e.g., N-acetyl vs N-azido). By cataloging the influence of these SAR on pharmacological properties of MGE analogues, this study outlines design considerations for tuning the pharmacological, physiochemical, and the toxicological parameters of this emerging class of small molecule drug candidates.

Original languageEnglish (US)
Pages (from-to)705-720
Number of pages16
JournalMolecular Pharmaceutics
Volume15
Issue number3
DOIs
StatePublished - Mar 5 2018

Fingerprint

Hexosamines
Volatile Fatty Acids
Pharmacology
Structure-Activity Relationship
Cataloging
Pharmaceutical Preparations
Cytochrome P-450 CYP3A
Butyrates
Drug Monitoring
Drug Design
P-Glycoprotein
Cardiac Myocytes
Computer Simulation
Toxicology
Acetates
Safety

Keywords

  • carbohydrate drug design
  • hERG
  • metabolic oligosaccharide engineering
  • P450
  • Pgp efflux

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering. / Saeui, Christopher T.; Liu, Lingshu; Urias, Esteban; Morrissette-Mcalmon, Justin; Bhattacharya, Rahul; Yarema, Kevin J.

In: Molecular Pharmaceutics, Vol. 15, No. 3, 05.03.2018, p. 705-720.

Research output: Contribution to journalArticle

Saeui, Christopher T. ; Liu, Lingshu ; Urias, Esteban ; Morrissette-Mcalmon, Justin ; Bhattacharya, Rahul ; Yarema, Kevin J. / Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering. In: Molecular Pharmaceutics. 2018 ; Vol. 15, No. 3. pp. 705-720.
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