Critical effect of peptide cyclization on the potency of peptide inhibitors against Dengue virus NS2B-NS3 protease.
Dengue virus (DENV) infection is a serious public health threat worldwide that demands effective treatment. In the search for potent virus protease inhibitors, several cone snail venoms were screened against serotype 2 DENV NS2B-NS3 protease, and one conotoxin, MrIA, was identified to have inhibitory activity. The inhibitory activity was attributed to a disulfide bond-mediated loop, from which rational optimization was made to improve the potency and stability. An eight-residue cyclic peptide inhibitor was finally obtained with high potency (inhibitory constant 2.2 μM), stability, and cell permeability. This inhibitor can thus serve as a good lead for DENV drug development. In addition, this work highlights the critical effect of peptide cyclization on the potency of oligopeptide inhibitors against DENV protease, which may advance the design of peptide inhibitors for homologous virus proteases.
Institute of Protein Research, Tongji University , Shanghai 200092, China.
Shaoqiong
S
Xu
Hua
H
Li
Xiaoxia
X
Shao
Chongxu
C
Fan
Bryan
B
Ericksen
Jinsong
J
Liu
Chengwu
C
Chi
Chunguang
C
Wang
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D002522:Chlorocebus aethiops; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology; D006224:Cricetinae; D003500:Cyclization; D003716:Dengue Virus / Q000201:enzymology*; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000085242:Viral Proteases
D000998:Antiviral Agents; D020916:Conotoxins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases