Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

Chong, Huihui; Xue, Yuan; Zhang, Chao; Cai, Lifeng; Cui, Sheng; Wang, Youchun; He, Yuxian

doi:10.1371/journal.pone.0032599

Cited by 59 publications

(51 citation statements)

References 55 publications

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“…Single-cycle infection assay A single-cycle infection assay was performed as described previously [26]. Briefly, HIV-1 pseudovirus was generated via cotransfection of 293T cells with an Envexpressing plasmid and a backbone plasmid pSG3 Denv that encodes Env-defective, luciferase-expressing HIV-1 genome.…”

Section: Methodsmentioning

confidence: 99%

Development of potent and long-acting HIV-1 fusion inhibitors

Chong

Wu²,

Sai³

et al. 2016

Aids

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Section: Methodsmentioning

confidence: 99%

Development of potent and long-acting HIV-1 fusion inhibitors

Chong

Wu²,

Sai³

et al. 2016

Aids

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“…HIV-1 entry and its inhibition were determined by single-cycle infection assay as described previously (38). Briefly, HIV-1 pseudovirus was generated by cotransfecting 293T cells with an Env-expressing plasmid and a backbone plasmid, pSG3…”

Section: Methodsmentioning

confidence: 99%

Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket

Sai

Chong

Qiu

et al. 2015

J Virol

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The deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N-and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors. IMPORTANCEEnfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.

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“…Both FB006 (IC 50 : 1.4 nM) and albuvirtide (IC 50 : 1.9 nM) are almost equally as potent as C34 (IC 50 : 2 nM) in inhibiting NL4-3 entry. However, they are much more potent than T20 (IC 50 : 62.5 nM) ( Figure 3A) [50,51].…”

Section: Review Of Patent Literaturementioning

confidence: 98%

Peptide fusion inhibitors targeting the HIV-1 gp41: a patent review (2009 – 2014)

Zhang

Li²,

Jiang

2014

Expert Opinion on Therapeutic Patents

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To improve enfuvirtide's anti-HIV efficacy, drug-resistance profile, half-life and pharmaceutical properties, the best approaches include the addition of the pocket-binding domain (PBD) to the N-terminus of T20 and linking of the M-T hook to the N-terminus of PBD, as well as conjugation of cholesterol, serum albumin-binding motif or gp120-binding fragment with a PBD-containing C-terminal heptad repeat-peptide. Therefore, sifuvirtide from Tianjin FusoGen Pharmaceuticals, Inc., albuvirtide from Frontier Biotechnologies Co., Ltd., cholesterol-conjugated HIV fusion inhibitor from the Institute of Pathogen Biology, Chinese Academy of Medical Science, 2DLT, a bivalent HIV fusion inhibitor/inactivator, and an enfuvirtide/sifuvirtide combination regimen from the New York Blood Center may all have potential as next-generation HIV fusion inhibitors targeting gp41 for clinical use.

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Biophysical Property and Broad Anti-HIV Activity of Albuvirtide, a 3-Maleimimidopropionic Acid-Modified Peptide Fusion Inhibitor

Cited by 59 publications

References 55 publications

Development of potent and long-acting HIV-1 fusion inhibitors

Development of potent and long-acting HIV-1 fusion inhibitors

Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket

Peptide fusion inhibitors targeting the HIV-1 gp41: a patent review (2009 – 2014)

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