Oral Presentation Royal Australian Chemical Institute National Congress 2026

Chemical Probes for Studying Nucleotide-Binding Proteins (136717)

Santosh Rudrawar 1
  1. School of Pharmacy and Medical Science, Griffith University, Gold Coast, QLD, Australia

This presentation focuses on the development of uridine- and adenine-based chemical probes as tools to interrogate the structure and function of biologically important nucleotide-binding proteins.

The enzyme MraY (phospho-MurNAc-pentapeptide translocase) plays a pivotal role in bacterial cell wall biosynthesis yet remains underexplored as a clinical antibacterial target [1-2] Naturally occurring nucleoside antibiotics inhibit MraY through mechanisms distinct from classical peptidoglycan biosynthesis inhibitors. The availability of X-ray crystal structures of MraY– ligand complexes, including apo (PDB:4J72),[3] tunicamycin-bound (PDB: 5JNQ),[4] and muraymycin-bound structures (PDB: 5CKR),5 has enabled structure-guided probe design.

To explore nucleoside antibiotics as a novel class of antibacterial agents, we have designed and synthesised simplified analogues of muraymycin nucleoside antibiotics. Muraymycins are known to exhibit potent antibacterial activity against both Gram-positive and Gram-negative bacteria [5]. Structure–activity relationship studies indicate that biological activity depends on the presence of a lipophilic side chain, together with key structural elements of the uridine core glycosylated at the 5′-position with an aminoribose unit. Guided by these insights, we synthesised a series of serine-templated muraymycin analogues incorporating these three pharmacophores [6]. Preliminary biological evaluation has revealed promising activity trends, which will be presented and discussed.

We have also developed adenine-derived chemical probes based on nicotinamide adenine dinucleotide (NAD+) metabolites, including cyclic adenosine diphosphate ribose (cADPR) and the recently identified isomers 2′-cADPR and 3′-cADPR [7].These cyclic nucleotides are emerging as a novel class of endogenous secondary messengers involved in cellular signalling [8]. Synthetic analogues of these adenine-based nucleotides have been prepared to enable the identification and functional characterisation of nucleotide-binding proteins, providing new tools to study NAD+-dependent signalling pathways.

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