Development and Characterization of Peptidic Fusion Inhibitors Derived from HIV‐1 gp41 with Partial D‐Amino Acid Substitutions

Abstract

The aim of this study was to design synthetic peptides with D-amino acid substitutions that mimic the human immunodeficiency virus (HIV) gp41 HR2 region. The objective was to develop new and active C34 analogue peptides by introducing D-amino acid point substitutions at nonessential sites for HR1-HR2 interaction without disrupting the structure of the peptide. Herein we report a study with C34L peptide analogues, including the enantiomer peptide C34D, the retro-inverso analogue (RI), and two peptides with D-amino acid point substitutions (C34M2 and C34M3). Our results show that, with the exception of RI, these peptides adopt an alpha-helical structure and are, like C34L, able to interact with HR1, mimicked by the N36 peptide. Furthermore, we show that modifications introduced in C34M2, but not in C34M3, enhance its resistance to trypsin-mediated hydrolysis and increase the stability of C34M2 in physiological medium. Interestingly, our results show that C34 peptide analogues C34M2 and C34M3, but not C34D and its RI analogue, retain their ability to inhibit HIV-1 replication with an efficiency similar to that of the C34L peptide. These data underscore the interest in using D-amino acids at specific sites in the C34 peptide sequence and may lead to a new strategy for the development of more stable and active anti-HIV-1 peptidic drugs.

Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: Towards the development of potential dual action antimalarials

“…One way to circumvent the limitations of peptidyl inhibitors is the use of retro-enantio peptides, i.e., analogs where all amino acids have a D configuration and are assembled in reversed order [24,25]. As these molecules have native side chain topology but reversed amide bonds, they theoretically allow enzyme-ligand contacts identical to those displayed by native peptides, while eluding recognition by other proteases (Fig.…”

Discovery of a potent peptidic cyclophilin A inhibitor Trp-Gly-Pro

“…The low anti-HIV-1 activity of the short peptide WGP in the in vitro testing system may be attributed to its instability in the cell culture which contains a variety of proteolytic enzymes. Appropriate chemical modification, such as the substitution of the natural amino acids with unnatural amino acids or D-amino acids [19,20], to increase the peptide stability may greatly improve its anti-HIV-1 efficiency.…”

Protein-Peptide Interactions Revolutionize Drug Development

“…Based on the fact that peptides derived from C-HR and N-HR regions of gp41 may serve as potent intibitors of HIV entry, intense research effort has been made for the rational design of different inhibitors based on these sequences. This also includes modifications such as incorporation of nonnatural and D-form amino acids (C34M3, [126]), synthesis of chimeric peptides (T1249, [123]) and even construction of fatty acid C-HR based conjugates (DP, [127]). For a detailed list, refer to the review by Naider and Anglister [121].…”