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 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.
Highlights
36.7 million people are living with HIV, with 20.9 million having access to antiretroviral therapy (ART) [1]
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
We explored the affinity between the PEGylated C34 and the NHR peptide N36, which contains the full binding region for C34, using a model suitable for the investigation of HIV fusion inhibitors the full binding region for C34, using a model suitable for the investigation of HIV fusion inhibitors [23]
Summary
36.7 million people are living with HIV, with 20.9 million having access to antiretroviral therapy (ART) [1]. In a generally accepted viral fusion model, the viral envelope surface glycoprotein gp120 binds sequentially to cell receptor CD4 and a coreceptor (CCR5 or CXCR4), triggering conformational changes in the core structure of gp41 [6], which, as determined by X-ray crystallography, reveals a stable 6-helix bundle (6-HB) consisting of 3 central N-terminal heptad repeat. Viruses 2019, 11, 811; doi:10.3390/v11090811 www.mdpi.com/journal/viruses (NHR) coiled coils and 3 C-terminal heptad repeat (CHR) helices packing into the hydrophobic NHR grooves as antiparallel [7]. In the past two decades, discovery of HIV-1 fusion inhibitory peptides from the NHR and CHR regions of gp opened an avenue for developing antiviral agents [8,9,10]
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