2008
DOI: 10.1074/jbc.m800200200
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Design and Evaluation of Sifuvirtide, a Novel HIV-1 Fusion Inhibitor

Abstract: Enfuvirtide (T20) is the first and only HIV-1 fusion inhibitor approved for clinical use, but it can easily induce drug resistance limiting its practical application. A novel anti-HIV peptide, termed sifuvirtide, was designed based on the three-dimensional structure of the HIV-1 gp41 fusogenic core conformation. Here we report its in vitro anti-HIV potency, its mechanism of action, as well as the results from Phase Ia clinical studies. We demonstrated that sifuvirtide inhibited HIV-1-mediated cellcell fusion i… Show more

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Cited by 197 publications
(219 citation statements)
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“…Such is indeed the case for C34, T20 (4), which spans part of the HR2 region and the sequence downstream (Fig. 1), and several other FI-targeting HR1 or HR2, including peptides, proteins, and small molecules (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”
mentioning
confidence: 99%
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“…Such is indeed the case for C34, T20 (4), which spans part of the HR2 region and the sequence downstream (Fig. 1), and several other FI-targeting HR1 or HR2, including peptides, proteins, and small molecules (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”
mentioning
confidence: 99%
“…Because C34 shows essentially no helical structure before folding onto HR1 to form the 6-helix bundle, HR2-derived peptides have been designed with enhanced helical structure in solution, which translates into greater strength of association with the HR1 coiled-coil and greater antiviral potency (8)(9)(10)24). Hybrids between C34 and T20 have also been pursued because the membrane-proximal region of gp41, included in T20, is beneficial for half-life (11). Although these peptides form 6-helix bundles with much increased stability with respect to C34, there appears to be a limit to the increase in potency that can be achieved by this route, with antiviral activity reaching a plateau over a wide range of bundle stability (8).…”
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confidence: 99%
“…In this fusion-active gp41 core structure, three N-terminal heptad repeat regions (NHR) form a central trimeric coiled coil, whereas three C-terminal heptad repeat regions (CHR) around the NHR pack as antiparallel helices into hydrophobic grooves (3)(4)(5)(6). A number of synthetic peptides derived from the NHR and CHR of gp41 can efficiently inhibit HIV-1 infection by competitively binding to the exposed NHR or CHR in the gp41 pre-hairpin state, hence blocking 6-HB formation in a dominant-negative manner (7)(8)(9)(10)(11)(12)(13)(14)(15). Among them, T20 (Enfuvirtide, Fuzeon) has been approved for clinical use as the first member of a new class of anti-HIV drugs, HIV fusion inhibitors (9,16,17).…”
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confidence: 99%
“…In succession to T20, the second-generation peptide fusion inhibitor T1249 was developed with increased antiviral potency, but its clinical development was halted due to the drug formulation problem (14,22,23). Among a series of more potent third generation fusion inhibitors (10,(12)(13)(14)(15), sifuvirtide (SFT) is one in advance stages. It has been evaluated by the phase I clinical trials and is currently under phase II clinical studies (13,24).…”
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