Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action
Abstract
1. Introduction
2. Materials and Methods
2.1. Ethics
2.2. Peptide Design Synthesis and Identification
2.3. Circular Dichroism (CD) Spectroscopy
2.4. Determination of gp41 6-HB Formation by Native Polyacrylamide Gel Electrophoresis (N-PAGE)
2.5. Cytotoxicity Assay
2.6. Inhibition of HIV-1 Env-Mediated Cell–Cell Fusion
2.7. Inhibition of HIV-1 Replication
2.8. Pharmacokinetics of Peptides in Rats
3. Results
3.1. Generation of High-Purity PEGylated HIV-1 Fusion Inhibitory Peptide
3.2. Binding of PEGylated C34 to NHR Forms Stable 6-HB
3.3. Inhibitory Potency of PEGylated C34 against Env-Mediated Cell–Cell Fusion and Infection of Laboratory-Adapted HIV-1 Strain with Low Cytotoxicity
3.4. PEGylated C34 Could Effectively Inhibit the Replication of the HIV-1 Subtypes Circulating in China
3.5. Decreased Resistance of T20-Induced HIV-1 Mutants to PEGylated HIV-1 Fusion Inhibitors
3.6. PEGylated C34 Displayed Prolonged Half-Life
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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HIV-1 Strains | T20 | C34 | PEG2kC34 | PEG5kC34 | ||||
---|---|---|---|---|---|---|---|---|
EC50 | n-Fold | EC50 | n-Fold | EC50 | n-Fold | EC50 | n-Fold | |
NL4-3 | 128.53 ± 21.06 | 1 | 0.98 ± 1.12 | 1 | 4.14 ± 1.89 | 1 | 4.59 ± 1.83 | 1 |
NL4-3V38A | 1361.21 ± 72.93 | 10.6 | 14.44 ± 5.44 | 14.7 | 34.10 ± 18.07 | 8.2 | 31.49 ± 4.71 | 6.9 |
NL4-3N43K | 764.40 ± 398.35 | 5.9 | 15.24 ± 5.73 | 15.6 | 30.03 ± 10.29 | 7.3 | 39.33 ± 32.10 | 8.6 |
NL4-3V38A/N42D | 424.70 ± 290.16 | 3.3 | 26.07 ± 4.77 | 26.6 | 59.39 ± 39.03 | 14.4 | 45.91 ± 38.62 | 10.0 |
NL4-3V38A/N42T | 780.06 ± 426.99 | 6.07 | 153.13 ± 19.80 | 156.3 | 114.71 ± 36.06 | 27.7 | 71.12 ± 38.07 | 15.5 |
Parameter | PEG2kC34 | PEG5kC34 |
---|---|---|
Rat, i.h., n = 4 | ||
Tmax (h) | 2.94 ± 1.30 | 3.88 ± 1.77 |
Cmax (μg/mL) | 10.37 ± 3.55 | 4.32 ± 1.88 |
t1/2 (h) | 2.57 ± 0.71 | 5.11 ± 3.54 |
AUC0-24h (μg/mL * h) | 39.75 ± 16.80 | 17.68 ± 6.98 |
AUCINF_obs (μg/mL * h) | 40.38 ± 16.75 | 15.56 ± 2.63 |
Vz_F_obs (ml/kg) | 773.42 ± 355.01 | 2688.46 ± 341.05 |
Cl_F_obs (ml/h/kg) | 353.43 ± 84.54 | 1033.79 ± 163.89 |
MRTlast (h) | 3.08 ± 0.55 | 3.75 ± 0.44 |
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Wang, C.; Cheng, S.; Zhang, Y.; Ding, Y.; Chong, H.; Xing, H.; Jiang, S.; Li, X.; Ma, L. Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action. Viruses 2019, 11, 811. https://doi.org/10.3390/v11090811
Wang C, Cheng S, Zhang Y, Ding Y, Chong H, Xing H, Jiang S, Li X, Ma L. Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action. Viruses. 2019; 11(9):811. https://doi.org/10.3390/v11090811
Chicago/Turabian StyleWang, Chen, Shuihong Cheng, Yuanyuan Zhang, Yibo Ding, Huihui Chong, Hui Xing, Shibo Jiang, Xuebing Li, and Liying Ma. 2019. "Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action" Viruses 11, no. 9: 811. https://doi.org/10.3390/v11090811
APA StyleWang, C., Cheng, S., Zhang, Y., Ding, Y., Chong, H., Xing, H., Jiang, S., Li, X., & Ma, L. (2019). Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action. Viruses, 11(9), 811. https://doi.org/10.3390/v11090811