Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds.
Human coxsackievirus (CV) belongs to the picornavirus family, which consists of over 200 medically relevant viruses. In picornavirus, a chymotrypsin-like protease (3C(pro)) is required for viral replication by processing the polyproteins, and thus it is regarded as an antiviral drug target. A 3C-like protease (3CL(pro)) also exists in human coronaviruses (CoV) such as 229E and the one causing severe acute respiratory syndrome (SARS). To combat SARS, we previously had developed peptidomimetic and zinc-coordinating inhibitors of 3CL(pro). As shown in the present study, some of these compounds were also found to be active against 3C(pro) of CV strain B3 (CVB3). Several crystal structures of 3C(pro) from CVB3 and 3CL(pro) from CoV-229E and SARS-CoV in complex with the inhibitors were solved. The zinc-coordinating inhibitor is tetrahedrally coordinated to the His(40)-Cys(147) catalytic dyad of CVB3 3C(pro). The presence of specific binding pockets for the residues of peptidomimetic inhibitors explains the binding specificity. Our results provide a structural basis for inhibitor optimization and development of potential drugs for antiviral therapies.
Lee
Cheng-Chung
CC
Structural Biology Program, Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan.
Kuo
Chih-Jung
CJ
Ko
Tzu-Ping
TP
Hsu
Min-Feng
MF
Tsui
Yao-Chen
YC
Chang
Shih-Cheng
SC
Yang
Syaulan
S
Chen
Shu-Jen
SJ
Chen
Hua-Chien
HC
Hsu
Ming-Chu
MC
Shih
Shin-Ru
SR
Liang
Po-Huang
PH
Wang
Andrew H-J
AH
D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry* / Q000627:therapeutic use; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000201:enzymology*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D015853:Cysteine Proteinase Inhibitors; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases; D015032:Zinc