GPMLS & BMC lecture - Cyclic Disulfide Prodrugs for Cytosol-Specific Drug Delivery

GPMLS & BMC lecture Friday 29 May at 12:20-13:20 in Árnagarður, room 301

Speaker: Dr. Gabor Butora, former director of Process Chemistry, Moderna, USA

Title: Cyclic Disulfide Prodrugs for Cytosol-Specific Drug Delivery

ABSTRACT: Bioreversible masking of negative charges that are naturally present in nucleoside monophosphates or oligonucleotides can be an effective tool for bypassing the often inefficient conversion of nucleosides to therapeutically active triphosphates as well as suppression of RNase-mediated degradation of larger therapeutic payloads. In this presentation, I will describe a cyclic-disulfide class of nucleoside prodrugs with a cytosol-specific reductive release trigger. In the first part of the presentation, I will describe the key event: a charge-dissipating reduction-triggered cyclo-deesterification of the cyclic-disulfide linking moiety, the relevant kinetics and other mechanistic considerations. In the second and third part, I will provide examples of applications relevant to antiviral nucleosides and larger therapeutic oligonucleotides, such as siRNAs.

Short Bio: Gabor Butora received his Masters Degree in Process Chemistry at the University of Chemistry & Technology in Prague, Czechoslovakia. He continued his studies at the Charles University, where he earned his Ph.D. in the field of biomedical chemistry. As a postdoctoral fellow at the Virginia Polytechnic Institute and State University in Blacksburg, VA he conducted research in the field of isoquinoline alkaloids and later, as a Research Associate at the Department of Chemistry, University of Florida, he spent time developing novel environmental friendly electrochemical methodologies. In 1997 Gabor joined the team of Merck Research Laboratories in Rahway, NJ where he conducted research in both Medicinal as well as Process chemistry, focusing mainly on nucleosides. He joined Moderna in 2015, where he established and led the Nucleoside Chemistry Team and later Moderna’s Process Chemistry R&D with significant contributions to development of Spikevax (Covid-19) and other modalities. Currently, he enjoys the little pleasures of retirement - spending time with his grandchildren, travel, photography, cooking and occasional consulting.