A Peptide-Based HIV-1 Fusion Inhibitor with Two Tail-Anchors and Palmitic Acid Exhibits Substantially Improved In Vitro and Ex Vivo Anti-HIV-1 Activity and Prolonged In Vivo Half-Life

Su, Shan; Rasquinha, Giselle; Du, Lanying; Wang, Qian; Xu, Wei; Li, Weihua; Lu, Lu; Jiang, Shibo

doi:10.3390/molecules24061134

Cited by 25 publications

(23 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasma samples were collected by centrifugation of the whole-blood samples (4500 g/min for 10 min at 4 °C) and were tested for ex vivo anti-HIV-1 activity as previously described [18]. The highest dilution-fold of the plasma sample causing 50% inhibition of HIV-1 infection was calculated, based on which the concentration of an active peptide in plasma was estimated [20] and its half-life and other pharmacokinetic parameters were calculated using MODFIT software [21].…”

Section: Methodsmentioning

confidence: 99%

Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

Wang

Cheng

Zhang

et al. 2019

Viruses

Self Cite

View full text Add to dashboard Cite

The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell–cell fusion with an effective concentration for 50% inhibition (EC50) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC50 of about 4–5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC50 of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t1/2) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t1/2 of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs.

show abstract

Section: Methodsmentioning

confidence: 99%

Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

Wang

Cheng

Zhang

et al. 2019

Viruses

Self Cite

View full text Add to dashboard Cite

show abstract

“…Viral entry inhibitors have been proven effective and safe for the treatment of viral infections (Jiang et al, 1993; Dando and Perry, 2003; Lu et al, 2016; Li et al, 2017; Su et al, 2019). We have previously reported that an HPV entry inhibitor, 3HP-β-LG, is highly effective in blocking the entry of HPV, both high- and low-risk types, into the host cell (Lu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The Underlying Mechanism of 3-Hydroxyphthalic Anhydride-Modified Bovine Beta-Lactoglobulin to Block Human Papillomavirus Entry Into the Host Cell

Chen

Zhu

et al. 2019

Front. Microbiol.

Self Cite

View full text Add to dashboard Cite

We have previously demonstrated that 3-hydroxyphthalic anhydride (3HP)-modified bovine beta-lactoglobulin (3HP-β-LG) is highly effective in inhibiting entry of pseudovirus (PsV) of high- and low-risk human papillomavirus (HPV) into the target cell. Intravaginally applied 3HP-β-LG-containing vaginal gel could significantly inhibit HPV infection and reduce viral load in the cervical region. However, we still do not understand the underlying molecular mechanism by which 3HP-β-LG is able to inhibit HPV infection. Here, though, we showed that 3HP-β-LG did not inactivate HPV PsV, but rather blocked entry of HPV PsV into the target cell via its interaction with virus, not cell. It bound to the positively charged region in the HPV L1 protein, suggesting that 3HP-β-LG binds to HPV L1 protein through the interaction between the negatively charged region in 3HP-β-LG and the positively charged region in HPV L1 protein, thus competitively blocking the binding of HPV to the receptor on the basement membrane in vaginal mucosa. Although 3HP-modified chicken ovalbumin (3HP-OVA) also carries high net negative charges, it exhibited no anti-HPV activity, suggesting that the interaction between 3HP-modified protein and HPV L1 protein relies on both electrostatic and matchable conformation of the binding sites in both proteins. When topically applied, 3HP-β-LG did not enter the host cell or blood circulation. These findings suggest that 3HP-β-LG targets HPV L1 protein and blocks HPV entry into the host cell, thus being safe and effective for topical application in the treatment of HPV infection.

show abstract

“…Consequently, peptide half-life was increased from 0.4249 to 6.967 h in rats (Feng et al 2018 ). Similarly, attachment of a palmitic acid (C16) chain to C-terminus of an anti-human immunodeficiency virus-1 (HIV-1) peptide YIK (EMTWEEWEKKIEEYIKKIEEILKKSQNQQLDL) extended its serum half-life from 1.3 to 5.9 h in mice (Su et al 2019 ).…”

Section: Npaas Incorporation For Improving Peptide Stability and Relamentioning

confidence: 99%

“…Similarly, conjugation of a C16 chain to the anti-HIV-1 peptide YIK, mentioned above, resulted in twofold improved potency. It was suggested that improved potency was due to enhanced binding of the peptides to the membrane of both host cells and viruses (Su et al 2019 ). It is important to mention that an amphiphilic peptide may contain either a C- or N-terminal alkyl tail and the biological activity can be dramatically affected by the position of the alkylation.…”

Section: Npaas Incorporation For Increasing Peptide Potencymentioning

confidence: 99%

Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

et al. 2020

View full text Add to dashboard Cite

With the development of modern chemistry and biology, non-proteinogenic amino acids (NPAAs) have become a powerful tool for developing peptide-based drug candidates. Drug-like properties of peptidic medicines, due to the smaller size and simpler structure compared to large proteins, can be changed fundamentally by introducing NPAAs in its sequence. While peptides composed of natural amino acids can be used as drug candidates, the majority have shown to be less stable in biological conditions. The impact of NPAA incorporation can be extremely beneficial in improving the stability, potency, permeability, and bioavailability of peptide-based therapies. Conversely, undesired effects such as toxicity or immunogenicity should also be considered. The impact of NPAAs in the development of peptide-based therapeutics is reviewed in this article. Further, numerous examples of peptides containing NPAAs are presented to highlight the ongoing development in peptide-based therapeutics.

show abstract

A Peptide-Based HIV-1 Fusion Inhibitor with Two Tail-Anchors and Palmitic Acid Exhibits Substantially Improved In Vitro and Ex Vivo Anti-HIV-1 Activity and Prolonged In Vivo Half-Life

Cited by 25 publications

References 47 publications

Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

The Underlying Mechanism of 3-Hydroxyphthalic Anhydride-Modified Bovine Beta-Lactoglobulin to Block Human Papillomavirus Entry Into the Host Cell

Impact of non-proteinogenic amino acids in the discovery and development of peptide therapeutics

Contact Info

Product

Resources

About