Helical peptides with disordered regions for measles viruses provide new generalized insights into fusion inhibitors
Kazushige Hirata,
Aoi Takahara,
Satoshi Suzuki,
Shumei Murakami,
Kumi Kawaji,
Akie Nishiyama,
Mina Sasano,
Mariko Shoji-Ueno,
Emiko Usui,
Kazutaka Murayama,
Hironori Hayashi,
Shinya Oishi,
Eiichi N. Kodama
Affiliations
Kazushige Hirata
Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Department of Clinical Laboratory Medicine, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan
Aoi Takahara
Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
Satoshi Suzuki
Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Shumei Murakami
Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Kumi Kawaji
Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Akie Nishiyama
Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Mina Sasano
Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Mariko Shoji-Ueno
Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Emiko Usui
Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Kazutaka Murayama
Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Hironori Hayashi
Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Corresponding author
Shinya Oishi
Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29, Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Medicinal Chemistry, Kyoto Pharmaceutical University, 1, Misasagi-Shichono-cho, Yamashina-ku, Kyoto 607-8412, Japan
Eiichi N. Kodama
Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Department of Infectious Diseases, Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan
Summary: Despite effective vaccines, measles virus (MeV) outbreaks occur sporadically. Therefore, developing anti-MeV agents remains important for suppressing MeV infections. We previously designed peptide-based MeV fusion inhibitors, M1 and M2, that target MeV class I fusion protein (F protein). Here, we developed a novel fusion inhibitor, MEK35, that exerts potent activity against M1/M2-resistant MeV variants. Comparing MEK35 to M1 derivatives revealed that combining disordered and helical elements was essential for overcoming M1/M2 resistance. Moreover, we propose a three-step antiviral process for peptide-based fusion inhibitors: (i) disordered peptides interact with F protein; (ii) the peptides adopt a partial helical conformation and bind to F protein through hydrophobic interactions; and (iii) subsequent interactions involving the disordered region of the peptides afford a peptide-F protein with a high-affinity peptide-F protein interaction. An M1-resistant substitution blocks the second step. These results should aid the development of novel viral fusion inhibitors targeting class I F protein.
