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T20 (enfuvirtide), a 36-mer peptide derived from the C-terminal heptad repeat region (CHR) of gp41, is the only clinically approved HIV-1 fusion inhibitor, but it easily induces drug resistance and is not active on HIV-2. In this study, we first demonstrated that the M-T hook structure was also vital to enhancing the binding stability and inhibitory activity of diverse CHR-based peptide inhibitors. We then designed a novel short peptide (23-mer), termed 2P23, by introducing the M-T hook structure, HIV-2 sequences, and salt bridge-forming residues. Promisingly, 2P23 was a highly stable helical peptide with high binding to the surrogate targets derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV). Consistent with this, 2P23 exhibited potent activity in inhibiting diverse subtypes of HIV-1 isolates, T20-resistant HIV-1 mutants, and a panel of primary HIV-2 isolates, HIV-2 mutants, and SIV isolates. Therefore, we conclude that 2P23 has high potential to be further developed for clinical use, and it is also an ideal tool for exploring the mechanisms of HIV-1\/2- and SIV-mediated membrane fusion.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The peptide drug T20 is the only approved HIV-1 fusion inhibitor, but it is not active on HIV-2 isolates, which have currently infected 1 to 2 million people and continue to spread worldwide. Recent studies have demonstrated that the M-T hook structure can greatly enhance the binding and antiviral activities of gp41 CHR-derived inhibitors, especially for short peptides that are otherwise inactive. By combining the hook structure, HIV-2 sequence, and salt bridge-based strategies, the short peptide 2P23 has been successfully designed. 2P23 exhibits prominent advantages over many other peptide fusion inhibitors, including its potent and broad activity on HIV-1, HIV-2, and even SIV isolates, its stability as a helical, oligomeric peptide, and its high binding to diverse targets. The small size of 2P23 would benefit its synthesis and significantly reduce production cost. Therefore, 2P23 is an ideal candidate for further development, and it also provides a novel tool for studying HIV-1\/2- and SIV-mediated cell fusion.<\/jats:p>","DOI":"10.1128\/jvi.01839-16","type":"journal-article","created":{"date-parts":[[2016,10,20]],"date-time":"2016-10-20T03:24:21Z","timestamp":1476933861000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":39,"title":["A Helical Short-Peptide Fusion Inhibitor with Highly Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus"],"prefix":"10.1128","volume":"91","author":[{"given":"Shengwen","family":"Xiong","sequence":"first","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}]},{"given":"Pedro","family":"Borrego","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal"}]},{"given":"Xiaohui","family":"Ding","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}]},{"given":"Yuanmei","family":"Zhu","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}]},{"given":"Andreia","family":"Martins","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal"}]},{"given":"Huihui","family":"Chong","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}]},{"given":"Nuno","family":"Taveira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal"},{"name":"Centro de Investiga\u00e7\u00e3o Interdisciplinar Egas Moniz, Instituto Superior de Ci\u00eancias da Sa\u00fade Egas Moniz, Caparica, Portugal"}]},{"given":"Yuxian","family":"He","sequence":"additional","affiliation":[{"name":"MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"},{"name":"Center for AIDS Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"AIDS by the numbers 2015","author":"UNAIDS","year":"2015","unstructured":"UNAIDS. 2015. 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