Exploratory studies on CA-15L, an anti-HIV active HIV-1 capsid fragment

Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors

“…A long alkyl chain and a PEG unit for the linker region were introduced into compound 1. Treatment of hexadecylamine (23) with succinic anhydride yielded the hemisuccinate (24) (Scheme 4), and subsequent treatment with N-hydroxysuccinimide gave the active ester (25), which was used in the next step without further purification (Scheme 5). Triethylene glycol monomethyl ether (26) was transformed to the tosylate (27), which was treated with diethylene glycol in the presence of sodium hydride to yield the alcohol (28).…”

“…There have been serious drawbacks, however, including the emergence of mutant viral strains with multidrug resistance, appearance of significant side effects, and the cost of the resulting drugs. In an attempt to solve these problems and enlarge the repertoire of anti-HIV-1 drugs, we have sought drugs with different mechanisms of action such as co-receptor CXCR4 antagonists, − CD4 mimics, − fusion inhibitors, − integrase inhibitors, , and inhibitors involving viral uncoating and viral assembly. − The viral entry steps are important targets for drug discovery because these are points at which an HIV-1 invasion can be blocked. HIV-1 entry into target cells is mediated by glycoproteins in its envelope, which consists of a surface subunit (gp120) and a noncovalently associated transmembrane subunit (gp41) .…”

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.…”

“…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.…”