Potent leads based on CA-19L, an anti-HIV active HIV-1 capsid fragment

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins

“…39,40 The MA and CA proteins are thought to be valid targets for inhibition of viral replication. Consequently, several MA and CA fragment derivatives were found to have anti-HIV activity in our [29][30][31][32][33] and other laboratories. [41][42][43][44] These peptide-derived inhibitors must penetrate cell membranes to inhibit the viral uncoating and assembly because these replication steps are based on the MA/CA degradation and oligomerization and are performed inside host cells.…”

“…The anti-HIV activity of the synthesized compounds was assessed based on their protection against HIV-1 (NL4-3 strain)induced cytopathogenicity in MT-4 cells using an MTT assay. [29][30][31][32][33] The cytotoxicity of these compounds was determined based on reduction of the viability of MT-4 cells, as determined by an MTT assay. These results are shown in Table 2.…”

“…In a persistent effort to resolve these problems and increase the alternatives and repertoires of anti-HIV-1 drugs, we have sought anti-HIV agents with various mechanisms of action such as coreceptor CXCR4 antagonists, [9][10][11][12][13][14][15] CD4 mimics, [16][17][18][19][20][21] fusion inhibitors, [22][23][24][25] integrase inhibitors [26][27][28] and inhibitors of viral uncoating and viral assembly. [29][30][31][32][33] Among these targets, inhibitors of viral uncoating and viral assembly [29][30][31][32][33] are the focus of this paper. The HIV-1 Gag precursor protein Pr55Gag produces the capsid (CA) protein, which is composed of N-and Cterminal domains (NTD/CTD) and is highly conserved among numerous HIV strains.…”

“…For this purpose, an octa-arginyl group 45 was added into the earlier peptide-derived inhibitors, described above, to enhance their cell membrane permeability. [29][30][31][32][33] Since small molecules might themselves have cell membrane permeability without an octa-arginyl group, it is desirable to search for small compounds with inhibitory activity against viral uncoating and assembly. Although several small compounds have been discovered to date, [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64] none has progressed to clinical trials with the exception of lenacapavir, formerly GS-6207.…”

Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins

“…Therefore, we have continued enormous efforts to resolve these issues and increase the alternatives and repertoires of anti-HIV-1 drugs, and sought anti-HIV agents with various mechanisms of action such as co-receptor CXCR4 antagonists, [9][10][11][12][13][14][15] CD4 mimics, [16][17][18][19][20][21] fusion inhibitors, [22][23][24][25] integrase inhibitors [26][27][28] and inhibitors of viral uncoating and viral assembly. [29][30][31][32][33] In the present study we focused on inhibitors of viral uncoating and viral assembly [29][30][31][32][33] among these attractive targets.…”