Fig. 1: GS-6207 is a potent CA-targeting inhibitor of HIV replication.
From: Clinical targeting of HIV capsid protein with a long-acting small molecule
a, GS-6207. b, Light scattering (absorbance at 350 nm) responses showing the rate and extent of in vitro CA (20 μM) assembly in 2 M NaCl, in the presence and absence of GS-6207. Data are representative of four independent experiments (n = 2 biological replicates each). c, Representative thin-section electron micrograph images of HIV-1 produced in the presence of 0.2% dimethyl sulfoxide (DMSO) (left), GS-6207 (15 nM) (middle) or the HIV-1 protease inhibitor atazanavir (500 nM) (right). Scale bars, 50 nm. d, Quantification for c. Data are mean ± s.d. from representative images of HIV-1 produced in one of two independent experiments. DMSO, n = 737 virions; GS-6207, n = 591 virions; atazanavir (ATV), n = 618 virions. P values in all figures are by unpaired two-tailed Student’s t-test with Welch’s correction. ****P < 0.0001. e, Inhibition of HIV-1 strain IIIB in MT-4 cells. Data are mean ± s.d. from 4 biological replicates in each of 8 to 115 independent experiments. GS-6207 (n = 8), rilpivirine (RPV) (n = 113), efavirenz (EFV) (n = 113), dolutegravir (DTG) (n = 115), bictegravir (BIC) (n = 20), ATV (n = 113), darunavir (DRV) (n = 60) and tenofovir alafenamide (TAF) (n = 15). ****P < 1 × 10−15. f, Inhibition of HIV-2 and HIV-1 group M (subtypes A–G, circulating recombinant forms (CRFs)), N and O clinical isolates. Data represent individual isolates (n = 3 biological replicates each). g, X-ray crystal structure of GS-6207–CA hexamer complex. Top and side views of CA hexamer (individual CA monomers coloured alternately in cyan and grey). The GS-6207 binding site, located between the NTD of one CA monomer and the CTD of an adjacent monomer, is boxed. h, Space-filling view of GS-6207 in its binding site (X-ray structure). i, Hydrogen bonds (dashed black lines, n = 7) and cation–π interactions (dashed yellow lines, n = 2) are shown between GS-6207 and CA residues.
