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

ABSTRACT: 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 ?-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.

SUBMITTER: Wang C

PROVIDER: S-EPMC6784077 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Wang Chen C Cheng Shuihong S Zhang Yuanyuan Y Ding Yibo Y Chong Huihui H Xing Hui H Jiang Shibo S Li Xuebing X Ma Liying L

Viruses 20190902 9

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 effect ...[more]

PMID: 31480738

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Project description:Angiotensin converting enzyme (ACE) inhibition offers a useful means of managing hypertension, because ACE inhibitors (ACEIs) are known to serve as agents with antihypertensive properties in addition to generating positive metabolic and cardioprotective outcomes. However, current ACEIs are linked to adverse consequences, and so there is a requirement for effective but safer compounds, which might be achieved through chemical synthesis or the isolation of naturally obtained bioactive molecules. Protein hydrolysates with ACEI activity can be produced by the combined pepsin and pancreatin proteolysis (to mimic gastrointestinal digestion) of longan seed protein. This study examined longan seed protein hydrolysates, obtained from a sequential 3 h digestion with pepsin and then pancreatin. The resulting hydrolysate underwent sequential ultrafiltration membrane fractionation with a 10, 5, and 3 kDa molecular weight cut-off (MWCO). The permeate derived from the <3 kDa MWCO demonstrated the highest ACEI activity. This permeate subsequently underwent separation by reverse-phase high performance liquid chromatography to give the main fractions on the basis of differing elution times. The ACEI IC50 values for these fractions were then identified. Quadrupole time-of-flight tandem mass spectrometry was employed to determine the peptide mass for the major peak (F 5), which was shown to be Glu-Thr-Ser-Gly-Met-Lys-Pro-Thr-Glu-Leu (ETSGMKPTEL) and Ile-Ser-Ser-Met-Gly-Ile-Leu-Val-Cys-Leu (ISSMGILVCL). These two peptides were stable over a temperature and pH range of -20 to 90 °C and 2-12, respectively, for 60 min. From the Lineweaver-Burk plot, both peptides inhibited ACE non-competitively. Molecular docking simulation of the peptides with ACE supported the formation of hydrogen bonds by the peptides with the ACE active pockets. This research indicates that it may be possible to use both of these peptides or longan seed protein hydrolysates in order to create ingredients for functional foods, or to produce pharmaceutical products, capable of lowering hypertension.

Dataset Information

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

Publications

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

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