Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy.

Xiaojie Zhu,Jianqing Xu,Rongguang Zhang,Zhiwu Sun,Qi Liu,Xiaoyan Zhang,Fei Yu,Qian Wang,Shibo Jiang,Chao Wang,Keliang Liu,Tianhong Zhang,Yun Zhu,Zhenqing Zhang,Lu Lu,Sheng Ye,Wei Xu,Shan Su,Lanying Du

doi:10.1038/srep13028

Abstract

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.

Highlights

Target cell membrane, exposing N-terminal heptad repeat (NHR) trimer, and forming the six-helix bundle (6-HB) structure. 6-HB contains three parallel NHR region and three antiparallel C-terminal heptad repeat (CHR) region, which brings the viral and cellular membranes into close proximity for fusion[1,2,3,4,5]
The preexisting antibodies in the sera of HIV-infected patients did not suppress, but enhanced the anti-HIV-1 activity of AP3. These results suggest that AP3 has potential for development as a new anti-HIV drug and confirm that this strategy can be used for designing artificial antiviral peptides against other enveloped viruses, such as SARS-CoV19, MERS-CoV20, and paramyxovirus[21]
The inhibitory activity of AP3 on infection by divergent primary HIV-1 isolates with distinct genotypes and phenotypes (R5 and X4) was higher than that of AP2 and T20 (Table 1)

Summary

Introduction

Target cell membrane, exposing N-terminal heptad repeat (NHR) trimer, and forming the six-helix bundle (6-HB) structure. 6-HB contains three parallel NHR region and three antiparallel C-terminal heptad repeat (CHR) region, which brings the viral and cellular membranes into close proximity for fusion[1,2,3,4,5]. Some antibodies targeting T20’s binding sites in gp[120] and gp[41] could attenuate T20-mediated inhibition of cell-cell fusion[15] To address these obstacles, many efforts have been made to optimize T20 and gp[41] CHR-derived peptides. Many efforts have been made to optimize T20 and gp[41] CHR-derived peptides Some of these peptides have better inhibitory activities against T20-resistant strains and/or longer half-life than T20. They still have the problem to cross-react with the preexisting antibodies in the sera of HIV-infected patients because they contain some native CHR sequences. These results suggest that AP3 has potential for development as a new anti-HIV drug and confirm that this strategy can be used for designing artificial antiviral peptides against other enveloped viruses, such as SARS-CoV19, MERS-CoV20, and paramyxovirus[21]

Methods

Results

Conclusion