Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring

Abstract

HIV-1 entry inhibition remains an urgent need for AIDS drug discovery and development. We previously reported the discovery of cyclic peptide triazoles (cPTs) that retain the HIV-1 irreversible inactivation functions of the parent linear peptides (PTs) and have massively increased proteolytic resistance. Here, in an initial structure-activity relationship investigation, we evaluated the effects of variations in key structural and functional components of the cPT scaffold in order to produce a platform for developing next-generation cPTs. Some structural elements, including stereochemistry around the cyclization residues and Ile and Trp side chains in the gp120-binding pharmacophore, exhibited relatively low tolerance for change, reflecting the importance of these components for function. In contrast, in the pharmacophore-central triazole position, the ferrocene moiety could be successfully replaced with smaller aromatic rings, where a p-methyl-phenyl methylene moiety gave cPT 24 with an IC50 value of 180 nM. Based on the observed activity of the biphenyl moiety when installed on the triazole ring (cPT 23, IC50 ∼ 269 nM), we further developed a new on-resin synthetic method to easily access the bi-aryl system during cPT synthesis, in good yields. A thiophene-containing cPT AAR029N2 (36) showed enhanced entropically favored binding to Env gp120 and improved antiviral activity (IC50 ∼ 100 nM) compared to the ferrocene-containing analogue. This study thus provides a crucial expansion of chemical space in the pharmacophore to use as a starting point, along with other allowable structural changes, to guide future optimization and minimization for this important class of HIV-1 killing agents.

The HIV-1 Env gp120 Inner Domain Shapes the Phe43 Cavity and the CD4 Binding Site

“…The CD4mc were analyzed, dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM, aliquoted, and stored at Ϫ80°C. Cyclic peptide triazoles (cPTs) AAR029N2 and AAR029N3 were synthesized, purified (Ͼ95% homogeneity by reverse-phase HPLC), and structurally validated as previously described (73,74). The cPTs were analyzed, dissolved in DMSO at a stock concentration of 10 mM, aliquoted, and stored at Ϫ80°C.…”

“…Finally, since changes in the gp120 inner domain layers in combination with changes at position 375 have a global effect on the CD4BS, we tested the sensitivity of our panel of CRF01_AE Env mutants to another class of Env antagonists targeting the CD4BS: cyclic peptide triazoles (cPTs) (73,74). Again, the introduction of the LM mutations in combination with a small residue at position 375 (LMϩHS and LMϩHT) in a CRF01_AE Env was found to dramatically increase the sensitivity to neutralization by all cPTs tested (AAR029N2 and AAR029N3) (Fig.…”

Pharmacokinetic stability of macrocyclic peptide triazole HIV‐1 inactivators alone and in liposomes

“…After cleavage and reverse‐phase HPLC purification, the N‐terminal AAR029b was reacted with FITC in DMF at room temperature to yield the FITC‐AAR029b that was purified using reverse‐phase HPLC. The N‐terminal was chosen for labeling based on previous observations which showed the solvent exposure of the N‐terminus.…”

“…In addition, a subclass of PTs, with a free Cys residue at the C terminus of PT and denoted peptide triazole thiols (PTTs), causes virus membrane lysis and release of luminal capsid protein p24 . More recently, small potent cyclic PTs (cPTs) were identified that hold great potential as anti‐HIV‐1 therapeutic leads. The added value of cPTs over linear PTs is that they are more resistant to proteolytic degradation while retaining high affinity and specificity for interaction with target envelope HIV‐1 glycoprotein gp120 and at the same time exhibiting no cellular toxicity.…”

Synthesis and antidiabetic evaluation of benzimidazole‐tethered 1,2,3‐triazoles

“…[8][9][10][11][12][13][14][15][16] Among different triazoles, 1,2,3triazoles particularly have a broad range of applications in the field of pharmaceutical and medicinal chemistry, and they are a part of many molecules reported as antidiabetic. [17][18][19][20][21][22][23][24] It has been reported that benzimidazole compounds, that is, 2-aryl benzimidazoles (A) and 2-(2chlorophenyl)-7-methyl-1H-benzo [d]imidazole (B), act as α-glucosidase inhibitors, [25][26][27] but there is still a need to discover some new analogs for improved inhibitory activity. Various studies have reported that by combining a benzimidazole ring with an electron-withdrawing group such as triazole, the biological activity gets enhanced.…”