Truncated Pneumolysin from <i>Streptococcus pneumoniae</i> as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions
Shun-Fu Chang,
Cheng-Nan Chen,
Jung-Chung Lin,
Hsin-Ell Wang,
Shigetarou Mori,
Jia-Je Li,
Chia-Kuang Yen,
Ching-Yun Hsu,
Chang-Phone Fung,
Pele Choi-Sing Chong,
Chih-Hsiang Leng,
Yi-Jun Ding,
Feng-Yee Chang,
L. Kristopher Siu
Affiliations
Shun-Fu Chang
Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan
Cheng-Nan Chen
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
Jung-Chung Lin
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
Hsin-Ell Wang
Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, Taiwan
Shigetarou Mori
Department of Bacteriology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Jia-Je Li
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
Chia-Kuang Yen
Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan
Ching-Yun Hsu
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
Chang-Phone Fung
Section of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
Pele Choi-Sing Chong
Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan
Chih-Hsiang Leng
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
Yi-Jun Ding
National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 350, Taiwan
Feng-Yee Chang
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
L. Kristopher Siu
Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan
Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)–TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.
