Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy.
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.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Xiaojie
X
Zhu
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Yun
Y
Zhu
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Sheng
S
Ye
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Qian
Q
Wang
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Wei
W
Xu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Shan
S
Su
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Zhiwu
Z
Sun
1] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China [2] Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10065, USA.
Fei
F
Yu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Qi
Q
Liu
Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
Chao
C
Wang
Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
Tianhong
T
Zhang
Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
Zhenqing
Z
Zhang
1] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China [2] Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201508, China.
Xiaoyan
X
Zhang
1] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China [2] Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 201508, China.
Jianqing
J
Xu
Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10065, USA.
Lanying
L
Du
Beijing Institute of Pharmacology &Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
Keliang
K
Liu
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China.
Lu
L
Lu
1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China [2] National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201210, China.
Rongguang
R
Zhang
1] Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China [2] Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10065, USA.
Shibo
S
Jiang
D000595:Amino Acid Sequence; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D018360:Crystallography, X-Ray; D019286:Endopeptidase K / Q000378:metabolism; D000077560:Enfuvirtide; D015483:HIV Antibodies / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000378:metabolism / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000302:isolation & purification; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D059748:Proteolysis / Q000187:drug effects; D017207:Rats, Sprague-Dawley
C000609765:AP3 antiviral peptide; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D000077560:Enfuvirtide; D019286:Endopeptidase K