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Aim: We previously designed an artificial HIV-1 fusion inhibitor, PBDtrp-m4HR. Here, we have added two amino acid residues that can form an M-T hook structure at its N-terminus, with the aim of improving its antiviral potency and drug-resistance profile. Methods: Peptides were synthesized and tested for their inhibitory activity on HIV-1 Env-mediated cell-cell fusion and infection by HIV-1 strains, including those resistant to T2635, the third generation HIV fusion inhibitor, as well as its binding affinity to the gp41 NHR-peptide N36. Results: MT-PBDtrp-m4HR exhibited improved inhibitory activity on HIV-1 infection and Env-mediated cell-cell fusion, displayed an improved drug-resistance profile and increased NHR-binding affinity. Conclusion: The added M-T hook is able to enhance or stabilize the interaction between MT-PBDtrp-m4HR and the viral gp41 NHR domain. Therefore, MT-PBDtrp-m4HR has potential to be further developed as a new HIV fusion inhibitor. The approach described in this study can also be used for designing artificial peptides against other enveloped viruses with class I membrane fusion proteins. [ABSTRACT FROM AUTHOR]

Abstract: We reported the design of fusion inhibitors with improved activity using a multivalent inhibitor design strategy. First, we chose C29 as the template sequence, which is a 29-mer peptide derived from HIV-1 gp41 CHR domain and has anti-HIV activity of IC50 118nM in a cell–cell fusion assay. We optimized the crosslink sites and linkers of the template peptide. We found that N-terminal crosslink caused activity improvement based on the multivalent co-operative effect. Especially, the IC50 of peptide (CAcaC29)2 was improved from 49.02 (monomeric form) to 5.71nM. Compared with long peptides, short peptides may be more suitable to analyze the co-operative effect. So we selected a shorter peptide C22 to synthesize the bivalent inhibitors. Due its weak helicity, no co-operative effect appeared. Therefore, we chose SC22EK, which were introduced salt bridges to consolidate the helicity based on the natural sequence C22. The cross-linked (CAcaSC22EK)2 was four times more potent than the monomer SC22EK in anti-HIV activity, with an IC50 value of 4.92nM close to the high active peptide fusion inhibitor C34. The strategy used in this study may be used to design new fusion inhibitors to interfere similar processes. [Copyright &y& Elsevier]

Abstract: The peptidic anti-HIV drug T20 (Fuzeon) and its analog C34 share a common heptad repeat (HR) sequence, but they have different functional domains, i.e., pocket- and lipid-binding domains (PBD and LBD, respectively). We hypothesize that novel anti-HIV peptides may be designed by using artificial sequences containing multiple copies of HR motifs plus zero, one or two functional domains. Surprisingly, we found that the peptides containing only the non-natural HR sequences could significantly inhibit HIV-1 infection, while addition of PBD and/or LBD to the peptides resulted in significant improvement of anti-HIV-1 activity. These results suggest that these artificial HR sequences, which may serve as structural domains, could be used as templates for the design of novel antiviral peptides against HIV and other viruses with class I fusion proteins. [Copyright &y& Elsevier]