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

Zhang, Dongmei; Li, Wen; Jiang, Shibo

doi:10.1517/13543776.2014.987752

Cited by 31 publications

(17 citation statements)

References 64 publications

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“…Especially, a cholesterolconjugated C34 (C34-Chol) showed approximately 50-fold more potent than C34 and yielded a plasma concentration 24 h after injection more than 300-fold higher than the measured IC 90 values in a mouse model [18]. Actually, we also created an extraordinarily potent cholesterol-conjugated peptide before C34-Chol was reported [31], which was based on the sequence of HIV-1 fusion inhibitor CP32M [32]. Conversely, Shai and coauthors [20][21][22] reported a conjugation strategy with sphingolipid, resulting in a group of NHR-derived shortpeptides that possessed markedly improved anti-HIV activity.…”

Section: Generation Of Cholesterol and Sphingolipidconjugated Peptidesmentioning

confidence: 93%

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

Chong

Wu²,

Sai³

et al. 2016

Aids

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Section: Generation Of Cholesterol and Sphingolipidconjugated Peptidesmentioning

confidence: 93%

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

Chong

Wu²,

Sai³

et al. 2016

Aids

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“…The sequence homology between HIV gp120 and snake neurotoxins, such as cobratoxin and bungarotoxin, had generated some antiretroviral patents [53][54][55]. Linking the gp120 fragment to the HIV peptide fusion inhibitors (fragments of gp41 ectodomains) was shown to improve their anti-HIV efficacy [56]. Besides structural homology, other action mechanisms of snake venoms against HIV are also discussed in the literature, such as catalytic/inhibitory activity through enzymes, binding interference (receptor/enzyme), and induction/interaction at the membrane level [50].…”

Section: Snake Venomsmentioning

confidence: 99%

Antiviral activity of animal venom peptides and related compounds

Mata

Mourão

Rangel

et al. 2017

J Venom Anim Toxins Incl Trop Dis

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Viruses exhibit rapid mutational capacity to trick and infect host cells, sometimes assisted through virus-coded peptides that counteract host cellular immune defense. Although a large number of compounds have been identified as inhibiting various viral infections and disease progression, it is urgent to achieve the discovery of more effective agents. Furthermore, proportionally to the great variety of diseases caused by viruses, very few viral vaccines are available, and not all are efficient. Thus, new antiviral substances obtained from natural products have been prospected, including those derived from venomous animals. Venoms are complex mixtures of hundreds of molecules, mostly peptides, that present a large array of biological activities and evolved to putatively target the biochemical machinery of different pathogens or host cellular structures. In addition, non-venomous compounds, such as some body fluids of invertebrate organisms, exhibit antiviral activity. This review provides a panorama of peptides described from animal venoms that present antiviral activity, thereby reinforcing them as important tools for the development of new therapeutic drugs.

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“…Peptide inhibitors made up of sequences from NHR or CHR (Table 1 ) when added exogenously bind to form heterogeneous 6HB molecules preventing a collapse of gp41 to the stable 6HB conformation and thereby, inhibiting membrane fusion and viral entry or cell-cell fusion [55-58] (for a recent review see [59]). Various fusion inhibitors targeting pre-hairpin intermediate structures have been under development [55, 56, 58-61].…”

Section: Introductionmentioning

confidence: 99%

“…The inhibitory peptide T20 (brand name: Fuzeon, generic name: enfuvirtide) is a peptide sequence from the CHR/MPER regions (residues 638-673) of gp41 [55, 57, 63], which was approved by the US FDA as an injectable HIV-1 fusion inhibitor in 2003. Since that time, many other peptides have shown great promise and are in continuing development (reviewed in [59, 75]).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41

Yi¹,

Fochtman²,

Rizzo³

et al. 2016

CHR

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Background The transmembrane subunit of the HIV envelope protein, gp41 is a vulnerable target to inhibit HIV entry. There is one fusion inhibitor T20 (brand name: Fuzeon, generic name: enfuvirtide) available by prescription. However, it has several drawbacks such as a high level of development of drug resistance, a short-half life in vivo, rapid renal clearance, low oral bioavailability, and it is only used as a salvage therapy. Therefore, investigators have been studying a variety of different modalities to attempt to overcome these limitations. Methods Comprehensive literature searches were performed on HIV gp41, inhibition mechanisms, and inhibitors. The latest structural information was collected, and multiple inhibition strategies targeting gp41 were reviewed. Results Many of the recent advances in inhibitors were peptide-based. Several creative modification strategies have also been performed to improve inhibitory efficacy of peptides and to overcome the drawbacks of T20 treatment. Small compounds have also been an area of intense research. There is a wide variety in development from those identified by virtual screens targeting specific regions of the protein to natural products. Finally, broadly neutralizing antibodies have also been important area of research. The inaccessible nature of the target regions for antibodies is a challenge, however, extensive efforts to develop better neutralizing antibodies are ongoing. Conclusion The fusogenic protein, gp41 has been extensively studied as a promising target to inhibit membrane fusion between the virus and target cells. At the same time, it is a challenging target because the vulnerable conformations of the protein are exposed only transiently. However, advances in biochemical, biophysical, structural, and immunological studies are coming together to move the field closer to an understanding of gp41 structure and function that will lead to the development of novel drugs and vaccines.

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

Cited by 31 publications

References 64 publications

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

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

Antiviral activity of animal venom peptides and related compounds

Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41

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