Lenacapavir: 2020 Small Molecule of the Year

Drug Hunter Team

We asked the global drug discovery community to vote on their favorite molecule from 2020, and the results are in. The community’s 2020 choice for Small Molecule of the Year is GS-6207 (lenacapavir), the awe-inspiring HIV capsid inhibitor published by Gilead Sciences in a 2020 issue of Nature.

The GSK RIPK2 PROTAC degrader received the second-highest number of votes, followed by a tie between BAY 1214784 and MRTX849. We’ll follow up later with more on these fascinating runners-up.

Oral antiretroviral agents have transformed HIV from a fatal to a more manageable chronic disease. However, suboptimal adherence to oral daily dosing regimens contributes to viral transmission and resistance generation. Individuals living with HIV that develops multidrug resistance have almost no treatment options.

GS-6207 potently disrupts the conserved HIV capsid protein with picomolar activity against all HIV-1 subtypes tested, providing a first-in-class option to treat and prevent drug-resistant HIV. The molecule has an exceptionally low rate of clearance in humans, showing sustained plasma exposure at antivirally active levels over 6 months after a single injection of 450 mg.

In 2019, the FDA granted GS-6207 Breakthrough Therapy Designation, and in 2020 Gilead announced results from the Ph. 2/3 CAPELLA trial showing that 88% of participants with multidrug resistant HIV receiving GS-6207 achieved viral load reduction over 14 days (vs. 17% in placebo).  During the J.P. Morgan Conference, Gilead announced that they planned to file an NDA for approval in the second half of 2021.

Drugging the HIV capsid was as hard as it looks. Unlike other HIV targets with approved drugs (protease, reverse transcriptase, integrase) the HIV-1 capsid protein isn’t an enzyme. The capsid is a shell that is made up of protein-protein interactions between over a thousand self-assembling capsid monomers. Inside the virion, the monomer is present at a concentration of ~4 mM, a significant barrier to optimization of competitive inhibitors.

The Gilead HIV capsid program was conceived in 2006, but internal HTS efforts didn’t lead to any useful starting matter. A breakthrough didn’t come until 2010, when a Pfizer virology team published an elegant study on the identification and mechanistic characterization of a new class of weakly-active capsid inhibitors in PLoS Pathogens. The Pfizer team was able to obtain an x-ray co-crystal structure with an engineered HIV capsid subunit, and proposed a binding model for their inhibitors in which each molecule of inhibitor binds 2 capsid subunits within a hexamer. Though the Pfizer molecule was weakly active (1.2 uM) and displayed cytotoxic activity, it was a helpful proof of concept that the HIV capsid might actually be targetable.

With a new class of chemical matter available, the Gilead team screened new molecules for effects on in vitro capsid assembly. They identified both inhibitors and accelerators of capsid assembly, but were never able to optimize inhibitors, likely due to the high concentration of competing capsid monomers.

Accelerators of capsid assembly turned out to be more tractable, and GS-6207 turns out to accelerate capsid assembly to produce malformed capsids that are distinct by electron microscopy (EM). This accelerator of malformation is extraordinarily potent against HIV replication in cells (105 pM). The accelerator mechanism of action is supported molecularly by a high-resolution X-ray structureof GS-6207 in complex with a cross-linked hexamer.

In the structure, six units of GS-6207 bind to six capsid monomers, with each GS-6207 molecule binding to the interface of two different monomers. It is fascinating that these compound-bound hexamers are still able to self-assemble into malformed structures as detected by electron microscopy.

Identifying compounds with low hepatic clearance was critical to the long half-life needed in Gilead’s target product profile. While the medicinal chemistry campaign hasn’t been described yet, the Gilead team does share that the turnover of compounds like GS-6207 was made so slow in primary human hepatocytes that 3H-radiolabeling of GS-6207 was needed to accurately measure its low turnover!

In our vote survey, we asked you what you liked about GS-6207, and here were some comments:

Drug Hunter would to love to host the Gilead team to present on the discovery of GS-6207 in a “Small Molecules of the Year” webinar or conference someday, and we’re sure the audience would love to hear from them as well. Until then, we’ll all be eagerly waiting new discovery details in future publications.

Update Feb. 28th: We’ve heard back from the team at Gilead that there are two upcoming talks on lenacapavir (ICAR + CROI) that have been added to the events page – more talks are upcoming, stay tuned.

Congratulations to the Gilead Sciences team on their success so far and we wish Gilead and their enrolled patients the best through the approval process.

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