The Discovery of PAXLOVID

Dr Dafydd Owen, Pfizer

It is our pleasure to invite you all to our RSC BMCS Lecture 2024, which will be delivered by Dr Dafydd Owen, Pfizer, on Wednesday 24/01/2024 at 15.00-16.00 (London time) in Electrical Engineering Keysight Technologies LT (1.52).

Biography: Dafydd Owen has twenty five years of experience as a medicinal chemist in the design and synthesis of drug-like molecules at Pfizer R&D in the UK and the United States. His current role focuses on a number of external collaborations using medicinal chemistry in new areas of science, in particular emerging protein families of interest. Most recently he led the multidisciplinary preclinical team that discovered PAXLOVID, the world’s first oral antiviral therapy authorized for the treatment of COVID-19. He obtained his first degree at Imperial College before moving to the University of Cambridge to gain a PhD under the supervision of Professor Steve Ley, FRS, CBE. Having won a research fellowship for postdoctoral work, he spent a year with Professor Leo Paquette at Ohio State University. During his research career he has delivered over one hundred invited lectures and is also an author on over seventy research papers and patents. He is a committed leader and communicator of science that has seen him present to KOLs and government. In 2009 he was the recipient of a Pfizer Global R&D People Leader Award. In the same year he was selected as an ACS Organic Division Young Industrial Investigator. In 2021 he received Pfizer's highest scientific awards as both an individual and as a team member - The Breakthrough Science and Innovation Prize. In 2022 he was recognized as an ACS Hero of Chemistry for his work on PAXLOVID. He has served on the Editorial Advisory Board of the Journal of Medicinal Chemistry and is a Board Member of the Structural Genomics Consortium. In July 2023 he wad awarded ‘The Honorary Degree of Doctor of Science at Bangor University for Outstanding Scholarship and Innovation’.

Talk title: The Discovery of PAXLOVID

Abstract: Small molecule inhibition of viral proteases has been a successful anti-viral therapeutic strategy in HIV and HCV. Structural insight on the SARS-CoV-2 main protease (Mpro) and previous small molecule experience with intravenous SARS-CoV-1 inhibitors gave a starting point for an oral Mpro inhibitor program in response to the COVID-19 outbreak. Designing and synthesizing molecules in a peptidomimetic chemotype, the team investigated a number of cysteine traps as reversibly covalent inhibitors, while looking to confer sufficient metabolic stability and permeability to attain oral bioavailability. Systematically challenging the need for hydrogen bond donors throughout the pharmacophore proved a successful strategy for enhancing permeability. This resulted in the discovery of PF-7321332, the first oral SARS-CoV-2 Mpro inhibitor to reach clinical development.1

PF-7321332 showed pan-human coronavirus activity with selectivity over human proteases Phase 1 healthy volunteer studies will be described, with and without combination of low dose ritonavir as a pharmacokinetic enhancer. The preclinical work to identify PF-7321332 (now known as nirmatrelvir) and the resulting Ph1 study was the basis for a combined Ph2/3 study in high-risk patients. Nirmatrelvir/ritonavir went on to receive emergency use authorization for the treatment of high risk COVID-19 patients in the United States as PAXLOVID in December of 2021, just 17 months after nirmatrelvir was first synthesized and received full FDA approval in May 2023.

The ‘start to finish’ drug discovery story will be presented from a medicinal chemist’s point of view.

 1.    Science (2021) 374, 1586–1593

Refreshment will be available in Chaston Chapman lounge after the talk. Please join us for this seminar and enjoy the excellent science from Prof. Andrei Khlobystov. 

This talk will be of interest to many colleagues outside the school, so please fee free to forward this invitation on.

**Note to all PhD students: Attendance of school seminars is expected from all PhD students and is part of your assessment in your transfer viva and annual review.

Best regards from the school seminar team,

David Santos-Carballal

Yi-Yeoun Kim

Bao Nguyen