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. 2023 Mar 24;120(13):e2222073120. doi: 10.1073/pnas.2222073120

Fig. 3.

Fig. 3.

Indoline CD4mcs inhibit HIV-1 entry more effectively than the previous lead indane CD4mc BNM-III-170. (A) Inhibition of infectivity of recombinant HIV-1 pseudotypes by CD4mc analogs. The bar graph shows the inhibitory activity of indoline CD4mcs against infection of recombinant virus pseudotyped with the Env of HIV-1JR-FL, normalized to that of the IC50 of BNM-III-170. The table beneath reports the IC50 values of indoline CD4mcs against viruses pseudotyped with the Envs of the AD8, JR-FL, and BG505 HIV-1 strains. Only three of the compounds (DY-III-075, CJF-IV-055, and CJF-IV-056) inhibited the control virus pseudotyped by the amphotropic murine leukemia virus (A-MLV) Env at concentrations of 300 µM or less. The table also reports the free energy of binding for the indoline CD4mc analogs predicted by an HIV-1BG505 gp120 docking model. (B) Comparison of the inhibition of infectivity by BNM-III-170 (39) and CJF-III-288 against a panel of recombinant viruses pseudotyped with the Envs of HIV-1 strains from multiple phylogenetic clades. Compared with BNM-III-170, CJF-III-288 displays an approximately 10-fold increase in potency for all HIV-1 pseudotypes examined, with the exception of clade A/E recombinants. Neither BNM-III-170 nor CJF-III-288 inhibited the control virus pseudotyped by the amphotropic murine leukemia virus (A-MLV) Env at concentrations of 100 µM or less. (C) The cell proliferation assay was conducted at varying concentrations of BNM-III-170 and indoline CD4mcs prepared from stock solutions in 100% DMSO (dimethyl sulfoxide). Compounds were incubated with TZM-bl cells for 72 h, after which the relative viability of the cells was evaluated with respect to the cells without treatment. The volume of DMSO used in the DMSO control corresponds to the volume of the CD4mc used at each indicated concentration. Measurements were performed in triplicate. Error bars indicate mean ± SEM. The levels of TZM-bl cell toxicity for the indoline CD4mcs are indicated as minimal (green), moderate (orange), or severe (red).