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- Title
IgG Fc-binding motif-conjugated HIV-1 fusion inhibitor exhibits improved potency and in vivo half-life: Potential application in combination with broad neutralizing antibodies.
- Authors
Bi, Wenwen; Xu, Wei; Cheng, Liang; Xue, Jing; Wang, Qian; Yu, Fei; Xia, Shuai; Wang, Qi; Li, Guangming; Qin, Chuan; Lu, Lu; Su, Lishan; Jiang, Shibo
- Abstract
The clinical application of conventional peptide drugs, such as the HIV-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. To overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24, by fusing it with the human IgG Fc-binding peptide (IBP). The newly engineered peptide IBP-CP24 exhibited potent and broad anti-HIV-1 activity with IC50 values ranging from 0.2 to 173.7 nM for inhibiting a broad spectrum of HIV-1 strains with different subtypes and tropisms, including those resistant to enfuvirtide. Most importantly, its half-life in the plasma of rhesus monkeys was 46.1 h, about 26- and 14-fold longer than that of CP24 (t1/2 = 1.7 h) and enfuvirtide (t1/2 = 3 h), respectively. IBP-CP24 intravenously administered in rhesus monkeys could not induce significant IBP-CP24-specific antibody response and it showed no obvious in vitro or in vivo toxicity. In the prophylactic study, humanized mice pretreated with IBP-CP24 were protected from HIV-1 infection. As a therapeutic treatment, coadministration of IBP-CP24 and normal human IgG to humanized mice with chronic HIV-1 infection resulted in a significant decrease of plasma viremia. Combining IBP-CP24 with a broad neutralizing antibody (bNAb) targeting CD4-binding site (CD4bs) in gp120 or a membrane proximal external region (MPER) in gp41 exhibited synergistic effect, resulting in significant dose-reduction of the bNAb and IBP-CP24. These results suggest that IBP-CP24 has the potential to be further developed as a new HIV-1 fusion inhibitor-based, long-acting anti-HIV drug that can be used alone or in combination with a bNAb for treatment and prevention of HIV-1 infection. Author summary: Enfuvirtide (T20) is the first US FDA-approved anti-HIV peptide drug. However, its clinical application is limited because of its short half-life and emergence of T20-resistant HIV strains. Here we developed a new strategy to prolong the half-life of a short anti-HIV peptide (CP24) by conjugating it with the human IgG Fc-binding peptide (IBP). IBP-CP24 exhibited potent and broad anti-HIV-1 activity and prolonged half-life, indicating its potential to be developed as a long-acting anti-HIV drug. Interestingly, combinational use of IBP-CP24 with a broad HIV neutralizing antibody, such as N6, showed synergistic anti-HIV-1 effect, suggesting that IBP-CP24 can be used together with N6 to treat HIV-1 infection because N6, as a biomissile carrying IBP-CP24, binds gp120 to make the first strike, and releases IBP-CP24 that binds gp41 to make the second strike to HIV-1. Therefore, combining IBP-CP24 with a bNAb may reduce the dose of the antibody and peptide, thus the cost of the treatment.
- Subjects
UNITED States. Food &; Drug Administration; ANTI-HIV agents; RHESUS monkeys; PEPTIDE drugs; IMMUNOGLOBULINS; HIV antibodies; MUSCARINIC acetylcholine receptors
- Publication
PLoS Pathogens, 2019, Vol 15, Issue 12, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008082