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  • Title: Artificial peptides conjugated with cholesterol and pocket-specific small molecules potently inhibit infection by laboratory-adapted and primary HIV-1 isolates and enfuvirtide-resistant HIV-1 strains.
    Author: Wang C, Shi W, Cai L, Lu L, Yu F, Wang Q, Jiang X, Xu X, Wang K, Xu L, Jiang S, Liu K.
    Journal: J Antimicrob Chemother; 2014 Jun; 69(6):1537-45. PubMed ID: 24500189.
    Abstract:
    OBJECTIVES: To develop new HIV-1 fusion inhibitors with improved antiviral activities and resistance profiles, we designed two categories of artificial peptides, each containing four heptad repeats (m4HR) conjugated with a pocket-specific small molecule (pssm) or pssm and cholesterol (chol), designated pssm-m4HR or pssm-m4HR-chol, respectively, and tested their anti-HIV-1 activity. METHODS: We synthesized the artificial peptides and conjugated these peptides with pssm and chol using a standard solid-phase Fmoc protocol and a chemoselective thioether conjugation method, respectively. We tested the inhibitory activities of the peptide conjugates against HIV-1 Env-mediated cell-cell fusion and infection by laboratory-adapted and primary HIV-1 isolates, and enfuvirtide-resistant HIV-1 strains using cell-cell fusion and p24 production assays, respectively. We assessed their cytotoxicity towards MT-2 cells using the XTT assay. RESULTS: We found that pssm-m4HR conjugates exhibited promising inhibitory activity against HIV-1 Env-mediated cell-cell fusion and laboratory-adapted HIV-1 replication with IC50 values at the low micromolar level, whereas the pssm-m4HR-chol conjugates exhibited dramatically increased anti-HIV-1 activities with IC50 values at the low nanomolar level. Some of the pssm-m4HR-chol conjugates (e.g. 5a and 5b) showed highly potent antiviral activity against infection by primary HIV-1 isolates and enfuvirtide-resistant HIV-1 strains. All the conjugates displayed no or low cytotoxicity towards MT-2 cells. The result of a prime/wash assay indicated pssm-m4HR-chol conjugates were strongly anchored to the membrane and sustained a potent inhibitory effect after washing. CONCLUSIONS: These results suggest this scaffold design is a promising strategy for developing novel peptide conjugates with improved antiviral activity against a broad spectrum of HIV-1 strains, including those highly resistant to enfuvirtide.
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