Trypsin inhibitory loop is an excellent lead structure to design serine protease inhibitors and antimicrobial peptides.
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
Jianxu
J
Biotoxin Unit of Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, China.
Zhang
Cheng
C
Xu
Xueqing
X
Wang
Jie
J
Yu
Haining
H
Lai
Ren
R
Gong
Weimin
W
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D010446:Peptide Fragments / Q000737:chemistry* / Q000302:isolation & purification; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D011487:Protein Conformation; D011898:Ranidae; D012867:Skin / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D010446:Peptide Fragments; D011480:Protease Inhibitors; D014361:Trypsin Inhibitors; D014357:Trypsin