We describe the in vitro pharmacological profile of GS-6207, a first-in-class HIV capsid (CA) inhibitor optimized for long-acting antiretroviral (ARV) treatment administered monthly or less frequently.
GS-6207 binding to HIV-1 CA hexamer was evaluated by surface plasmon resonance and x-ray crystallography. Antiviral potency and cytotoxicity were assessed in human T-cell lines and primary cells. HIV-1 and -2 laboratory strains and clinical isolates as well as HIV-1 recombinant mutants resistant to other ARV drug classes were used for antiviral profiling. Effect of the multiplicity of infection (MOI) on antiviral potency was tested using a reporter HIV-1. Cytotoxicity was profiled in 4 non-target human cell lines and primary hepatocytes. GS-6207 activity was evaluated in combination with marketed classes of ARVs.
GS-6207 binds with high affinity to CA hexamers (KD = 0.2 nM) at the interface between two adjacent CA monomers. GS-6207 displays potent and selective antiviral activity in MT-4 cells (EC50 = 0.1 nM, CC50 = 27 µM) and exhibits a mean EC50 of 0.05 nM (0.02 – 0.16 nM) in human PBMCs against 23 HIV-1 clinical isolates spanning all major subtypes. The human serum protein-adjusted EC95 for GS-6207 (4 nM) is >10-fold lower than that of efavirenz (EFV), rilpivirine, dolutegravir (DTG) and atazanavir (ATV). In primary human CD4+ T-cells and macrophages, GS-6207 is >10-fold more potent and >22-fold more selective than EFV, DTG and ATV. GS-6207 also suppresses HIV-2 replication. As with other ARVs, GS-6207 antiviral activity decreases with increasing MOI but remains 5- to >100-fold more potent than 4 commonly used ARVs. GS-6207 exhibits low cytotoxicity in 4 human cell lines and primary hepatocytes (CC50 > 44 µM) and shows synergistic antiviral activity when combined pairwise with agents from each of 4 marketed ARV classes. Finally, GS-6207 retains full potency against a broad range of HIV-1 mutants resistant to other ARV classes, including those with naturally occurring Gag polymorphisms conferring resistance to maturation inhibitors.
GS-6207 is a novel HIV capsid inhibitor with picomolar potency and a unique resistance and pharmacokinetic (PK) profile that make it a suitable candidate for a low-dose long-acting subcutaneous administration to treat HIV-1 infection, including variants resistant to current ARV therapies. The safety and PK of GS-6207 is now being evaluated in healthy human subjects.