Chemical Biology Seminar: John Link, Gilead Sciences

Photo of John Link
Date Range
Wed April 19th 2023, 3:00 - 4:00pm
Sapp Center Auditorium 111

About the Seminar

The Discovery and Development of Lenacapavir (GS-6207): a Twice-Yearly Injectable or Orally Dosed First-in-Class HIV Capsid Inhibitor

Lenacapavir is a first-in-class HIV capsid disrupting drug and represents a new antiviral modality. Prior to lenacapavir there has been no approved capsid targeting drug for any virus. Lenacapavir disrupts the self-assembly of the 1500 identical protein subunits that comprise the >37 million Dalton HIV capsid. Despite the challenges in disrupting a protein-protein interaction target on this large scale, lenacapavir is the most potent approved HIV drug with an EC50 of 100 pM in HIV-1 infected MT-4 T-cells.

Our program to target HIV capsid initiated over 16 years ago and was intensively focused on driving extreme antiviral potency and an exceedingly high level of metabolic stability. While our original goal was to discover a once-daily orally administered HIV capsid targeting drug, the exceptional potency, metabolic stability, and properties of lenacapavir have opened avenues in both oral and parenteral dosing. Despite breaking most “rules” of oral bioavailability, lenacapavir is approved as an oral lead-in to parenteral dosing and is also undergoing Phase 3 clinical trials in all-oral combination therapy.

With its novel mechanism of action, lenacapavir is potent against virus resistant to prior antiviral classes. Lenacapavir is approved as Sunlenca®, a twice-yearly parenterally dosed therapy for heavily treatment experienced people living with HIV with multidrug resistant virus. Additionally, twice-yearly lenacapavir is being studied for pre-exposure prophylaxis (PrEP) in two Phase 3 clinical trials (PURPOSE 1 and 2). Many individuals at risk of acquiring HIV face stigma, discrimination and healthcare inequity leading to barriers to the uptake of daily oral PrEP. With its infrequent twice-yearly dosing, lenacapavir provides a private, low resource burden therapeutic option that has the potential to play an important role in efforts to end the AIDS epidemic.

The discovery and development of lenacapavir will be described.

About the Speaker

John O. Link received his PhD in Organic Chemistry from EJ Corey’s lab at Harvard University (Corey-Link Reaction). At Syntex/Roche he elucidated the inhibition mechanism of the immunosuppressant drug CellCept®, along with the enzymatic mechanism of its target IMP dehydrogenase. At Arris/Celera he was co-inventor of several covalent-reversable serine and cysteine protease inhibitors that entered clinical trials. As Vice President of Medicinal Chemistry at Gilead Sciences, John is co-inventor of four approved drugs discovered in his research group: the curative hepatitis C drugs ledipasvir (NS5A inhibitor), velpatasvir (pan-genotypic NS5A inhibitor), and voxilaprevir (pan-genotypic NS3/4A protease inhibitor), components in Harvoni® Epclusa® and Vosevi®, and the first-in-class twice-yearly dosed HIV capsid inhibitor lenacapavir (Sunlenca®) which is the only approved drug that targets a viral capsid. John was project leader for the ledipasvir, velpatasvir and lenacapavir programs.

John was awarded the American Chemical Society’s 2015 Heroes of Chemistry for his contributions to the discovery of Harvoni® and the 2017 inaugural Male Ally Award from the Women at Gilead employee resource group.