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Trypsin inhibitory loop is an excellent lead structure to design serine protease inhibitors and antimicrobial peptides

Jianxu Li^*,¶,1, Cheng Zhang^,||,1, Xueqing Xu^*,¶,1, Jie Wang^,||, Haining Yu, Ren Lai^*,,2 and Weimin Gong^,2

^* Biotoxin Units of Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China;

Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;

Key Laboratory of Microbiological Engineering of Agricultural Environment, Ministry of Agriculture, Life Sciences College of Nanjing Agricultural University, Nanjing, Jiangsu, China;

College of Life Sciences of Heibei Normal University, Shijiazhuang, Hebei, China;

^|| School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China; and

^¶ Graduate School of the Chinese Academy of Sciences, Beijing, China

²Correspondence: R.L.: Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China. E-mail: rlai{at}mail.kiz.ac.cn; W.G.: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. E-mail: wgong{at}ibp.ac.cn

The disulfide-bridged hendecapeptide (CWTKSIPPKPC) loop, derived from an amphibian skin peptide, is found to have strong trypsin inhibitory capability. This loop, called the trypsin inhibitory loop (TIL), appears to be the smallest serine protease inhibitor known. A series of synthetic peptides derived from this loop also exhibits trypsin inhibitory activity; some peptides even exhibit both antimicrobial and trypsin inhibitory activities. Antimicrobial peptides are attractive candidates for producing novel antibiotics, but their sensitivity to trypsin-like proteases appreciably limits their application. Bifunctional peptides with both antimicrobial and trypsin inhibitory activities could be ideal candidates for clinical antibiotics, since these reported synthetic peptides have shown resistance against trypsin. The crystal structure of a complex of trypsin with one TIL derivative is solved. The concept of TIL is introduced in this paper. Novel trypsin inhibitors or antimicrobial peptides can be designed readily on the basis of the TIL. Furthermore, functional analysis and a precursor comparison suggest that serine protease inhibitors may have a common ancestor with antimicrobial peptides.—Li, J., Zhang, C,, Xu, X., Wang, J., Yu, H., Lai, R., Gong, W. Trypsin inhibitory loop is an excellent lead structure to design serine protease inhibitors and antimicrobial peptides.

Key Words: trypsin resistance