Invité équipe B. Canard: Lawrence Harris, Ferrier Research Institute, Victoria Univ. of Wellington – « The development of new classes of antiviral nucleosides »

Abstract

Broad-spectrum antiviral nucleosides are an important class of molecules with proven potential to treat viral diseases. Both RNA and DNA viruses are susceptible to these modified nucleotides that interfere with viral nucleic acid replication. This talk outlines our efforts to develop two new classes of broad-spectrum antivirals (BSAs) based on (i) Galidesivir (Immucillin A, BCX4430) – a known synthetic imino-C-nucleoside with broad-spectrum activity, and (ii) the recently discovered, antiviral ribonucleotide product of the interferon-inducible protein viperin, namely 3’-deoxy-3’,4’-didehydrocytidine triphosphate (ddhCTP).

Broad screening of novel compounds for antiviral activity in cell-based assays reveals that subtle modifications to the nucleobase component of imino-C-nucleosides can profoundly enhance or reduce the activity. One compound that exhibited sub-micromolar activity against multiple strains of influenza A and B viruses and excellent selectivity indexes was assessed against influenza A (H1N1) in preliminary in vivo studies in BALB/c mice. However, it displayed significant toxicity necessitating further development. Through further synthetic modification, attempts to lower the intrinsic toxicity of this molecule have delivered new compounds with improved safety profiles in vitro. Work is ongoing to further develop these promising new antiviral leads.

Biography

Dr. Lawrence Harris is a Principal Scientist at the Ferrier Research Institute in Wellington, New Zealand, where he leads research collaborative research at the interface of synthetic organic chemistry and biology. He completed his PhD in synthetic organic chemistry at the University of Oxford in 2009 before relocating to New Zealand to join the Ferrier Research Institute of Victoria University of Wellington.

A central theme of Dr. Harris’s research is the development of new synthetic methodologies, alongside the design and synthesis of biologically active molecules, particularly enzyme inhibitors for infectious disease applications. His work spans both antiviral and antibacterial discovery. Since 2019, his team has developed new methodologies to access antiviral nucleoside and nucleotide analogues inspired by the endogenous antiviral ddhCTP and the broad-spectrum compound galidesivir (BCX4430), which originated at the Ferrier Institute. He has led two major New Zealand Ministry of Business, Innovation and Employment-funded antiviral development programmes in this area and is one of the founders of the Aotearoa New Zealand Antiviral Research Network. In parallel, he designs mechanism-based inhibitors targeting essential bacterial enzymes, working closely with biochemists to develop selective, narrow-spectrum antibiotics.

He has also led industry collaborations, notably working with New Zealand Pharmaceuticals for six years to develop bile acid therapeutics and scalable synthetic routes for medicinal chemistry libraries targeting metabolic and neurodegenerative diseases.

Dr. Harris is passionate about advancing synthetic organic chemistry methodology and applying these innovations to the discovery and development of new therapeutics.

https://scholar.google.com/citations?hl=en&user=TfVaAcwAAAAJ&view_op=list_works&sortby=pubdate