A first-in-class HIV-1 capsid inhibitor interrupts replication at two steps of the viral lifecycle and has pharmacokinetic properties that may permit once-monthly or less frequent dosing. A candidate compound has picomolar activity against HIV-1 representing all major subtypes.
The HIV capsid is the cone-shaped HIV RNA-bearing core of newly formed viral particles. This core gets unwrapped inside infected cells, and unleashed viral RNA goes on to mesh with host-cell DNA. Although the capsid plays essential roles in the viral life cycle, it remains to be exploited as an antiretroviral target. Researchers at Gilead Sciences have begun developing and testing a set of metabolically stable capsid inhibitors that may lend themselves to slow-release parenteral administration.
The first candidate in this class, labeled GS-CA1, was more potent than efavirenz (Sustiva, Stocrin), atazanavir (Reyataz) or dolutegravir (Tivicay, DTG) in cell studies involving CD4 T lymphocytes, macrophages and peripheral blood mononuclear cells (PBMCs). Compared with dolutegravir, for example, GS-CA1 had substantially greater potency indicated by lower 50% effective concentrations (EC50) in CD4 cells (60 versus 1,000 pM), macrophages (100 versus 1,900 pM) and PBMCs (140 versus 1,200 pM). Cell studies also indicated that GS-CA1 has no measurable cytotoxicity in target and nontarget primary cells.
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GS-CA1 potency averaged 140 pM in PBMCs against HIV-1 subtypes A, B, C, D, E, F, G, CRF01_AE and CRF02_AG. The capsid inhibitor class being studied retained full activity against HIV-1 resistant to licensed antiretrovirals. These capsid inhibitors bind to a highly conserved interface between two adjacent monomers within the capsid hexamer, the 6-monomer structures that make up the capsid core. GS-CA1 selects for capsid mutations L56I, M66I, Q67H, N74D or A105E. All these mutations occur at the capsid inhibitor binding site with fold changes in EC50 relative to wild-type virus ranging from 7.7-fold to more than 2,270-fold. Mutants with the greatest fold change relative to wild-type virus have reduced fitness.
Mechanistic studies determined that GS-CA1 interrupts HIV-1 replication at two discrete steps of the viral life cycle: at an EC50 of 240 pM, the compound inhibits capsid core assembly as the cell-free viral particle matures; and at an EC50 of 53 pM, it inhibits integration of viral RNA into the target cell nucleus after the capsid disassembles inside infected cells. In these analyses, combined anti-HIV activity for a full single round of replication measured 85 pM.
Pharmacokinetic analyses in rats showed that a single subcutaneous injection of GS-CA1 maintained plasma levels above the protein-adjusted EC95 for more than 10 weeks. This finding suggests that a monthly or less frequent dosing interval may be possible in humans. Pharmacokinetic profiles in multiple species indicate low systemic drug clearances (0.08 to 0.33 L/h/kg) and long half-lives (7.2 to 18.7 h).
Gilead investigators conclude that the compound selected for clinical development has high potency, low metabolic clearance and slow-release kinetics after injection that support low-dose long-acting administration.