Structural basis for the dimerization and substrate recognition specificity of porcine epidemic diarrhea virus 3C-like protease

Ye, Gang; Deng, Feng; Shen, Zhou; Luo, Rui; Zhao, Ling; Xiao, Shaobo; Fu, Zhen F.; Peng, Guiqing

doi:10.1016/j.virol.2016.04.018

Cited by 45 publications

(88 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5A and B). Otherwise, previous studies have shown that the substrate-binding sites and active sites of the 3CLSP and 3CL protease are located between domains I and II in their structures (Tian et al, 2009;Ye et al, 2016). The amino acid residue His39 in 3CLSP (corresponding to His41 of 3CL protease) plays a vital role in substrate combination and catalysis.…”

Section: Discussionmentioning

confidence: 98%

“…In the 3CLSP and Y. Shi et al Veterinary Microbiology 213 (2018) 114-122 3CL protease, the S1 specificity pocket is essential for recognition of the side chain of the substrate P1 residue and determination of the enzyme's preference (Tian et al, 2009;Ye et al, 2016). Hence, the residues of S1 specificity pockets were selected as targets for molecule docking.…”

Section: Discussionmentioning

confidence: 99%

“…5A and B). The complex models were initially positioned based on the X-ray structures (Streptomyces griseus proteinase E, SGPE, PDB code: 1HPG; PEDV nsp5: 4ZUH) (Nienaber et al, 1993;Ye et al, 2016). Grid maps of 40 × 40 × 40 grid points, centered on the substrates of the complex structures, covered the binding pockets.…”

Section: Potential Binding Sitesmentioning

confidence: 99%

“…In the PRRSV and PEDV genome, ORF1a and ORF1b comprise approximately 80% of the genome and encode polyproteins (pp1a and pp1b) that are cleaved by viral proteases into intermediate and mature nonstructural proteins (Ziebuhr et al, 2000;Gorbalenya et al, 2006). The viral proteases involved in polyprotein cleavage are papain-like proteases (PL1pro and PL2pro) and a 3CL serine protease (PRRSV nsp4; 3CLSP)/3C-like (PEDV nsp5; 3CL) protease (Tian et al, 2009;Ye et al, 2016). During replication, the PL1pro and PL2pro proteases cleave the N-proximal region of pp1a/pp1ab, and the 3CLSP/3CL protease cleaves the viral polyprotein at other conserved inter-domain junctions (Tian et al, 2009;Ye et al, 2016).…”

mentioning

confidence: 99%

“…The viral proteases involved in polyprotein cleavage are papain-like proteases (PL1pro and PL2pro) and a 3CL serine protease (PRRSV nsp4; 3CLSP)/3C-like (PEDV nsp5; 3CL) protease (Tian et al, 2009;Ye et al, 2016). During replication, the PL1pro and PL2pro proteases cleave the N-proximal region of pp1a/pp1ab, and the 3CLSP/3CL protease cleaves the viral polyprotein at other conserved inter-domain junctions (Tian et al, 2009;Ye et al, 2016). The viral 3CLSP/3CL proteases play an essential role in artertivirus and coronavirus replication; therefore, they have received much attention as potential key antiviral targets (including TGEV, FIPV, IBV and SARS-CoV) (Anand et al, 2002;Kim et al, 2013;Lee et al, 2007;Xue et al, 2008).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

Shi

Lei

et al. 2018

Veterinary Microbiology

Self Cite

View full text Add to dashboard Cite

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine epidemic diarrhea virus (PEDV) are highly virulent and contagious porcine pathogens that cause tremendous economic losses to the swine industry worldwide. Currently, there is no effective treatment for PRRSV and PEDV, and commercial vaccines do not induce sterilizing immunity. In this study, we screened a library of 1000 compounds and identified two specific inhibitors, designated compounds 2 and 3, which target the PRRSV 3C-like serine protease (3CLSP). First, we evaluated the inhibitory effects of compounds 2 and 3 on PRRSV 3CLSP activity. Next, we determined the anti-PRRSV capacity of compounds 2 and 3 in MARC-145 cells and obtained EC and CC values of 57μM (CC=479.9μM) and 56.8μM (CC=482.8μM), respectively. Importantly, compounds 2 and 3 also targeted the PEDV 3C-like protease (3CL protease) and inhibited PEDV replication, showing EC and CC values of 100μM (CC=533.8μM) and 57.9μM (CC=522.3μM), respectively. Finally, our results indicated that the active sites (His39 in 3CLSP and His41 in 3CL protease) were conservative, and contacted compounds 2 and 3 via hydrogen bonds and hydrophobic forces in the putative substrate-binding models. In summary, compounds 2 and 3 exhibit broad-spectrum antiviral activity and may facilitate the development of antiviral drugs against PRRSV and PEDV.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Potential Binding Sitesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

Shi

Lei

et al. 2018

Veterinary Microbiology

Self Cite

View full text Add to dashboard Cite

show abstract

What coronavirus 3C‐like protease tells us: From structure, substrate selectivity, to inhibitor design

Xiong

Zhao

et al. 2021

Medicinal Research Reviews

110

View full text Add to dashboard Cite

The emergence of a variety of coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, the ongoing pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has led to more than 70 million infections and over 1.6 million of deaths worldwide in the past few months. None of the efficacious antiviral agents against human CoVs have been approved yet. 3C‐like protease (3CL pro ) is an attractive target for antiviral intervention due to its essential role in processing polyproteins translated from viral RNA, and its conserved structural feature and substrate specificity among CoVs in spite of the sequence variation. This review focuses on all available crystal structures of 12 CoV 3CL pro s and their inhibitors, and intends to provide a comprehensive understanding of this protease from multiple aspects including its structural features, substrate specificity, inhibitor binding modes, and more importantly, to recapitulate the similarity and diversity among different CoV 3CL pro s and the structure–activity relationship of various types of inhibitors. Such an attempt could gain a deep insight into the inhibition mechanisms and drive future structure‐based drug discovery targeting 3CL pro s.

show abstract

Two Inhibitors Against the 3C-Like Proteases of Swine Coronavirus and Feline Coronavirus

Zhou

Han

et al. 2021

Virol. Sin.

Self Cite

View full text Add to dashboard Cite

Coronaviruses (CoVs) are important human and animal pathogens that cause respiratory and gastrointestinal diseases. Porcine epidemic diarrhoea (PED), characterized by severe diarrhoea and vomiting in pigs, is a highly lethal disease caused by porcine epidemic diarrhoea virus (PEDV) and causes substantial losses in the swine industry worldwide. However, currently available commercial drugs have not shown great therapeutic effects. In this study, a fluorescence resonance energy transfer (FRET)-based assay was applied to screen a library containing 1,590 compounds and identified two compounds, 3-(aminocarbonyl)-1-phenylpyridinium and 2,3-dichloronaphthoquinone, that target the 3C-like protease (3CL pro ) of PEDV. These compounds are of low molecular weight (MW) and greatly inhibited the activity of this enzyme (IC 50 values were obtained in this study). Furthermore, these compounds exhibited antiviral capacity against another member of the CoV family, feline infectious peritonitis virus (FIPV). Here, the inhibitory effects of these compounds against CoVs on Vero cells and feline kidney cells were identified (with EC 50 values) and cell viability assays were performed. The results of putative molecular docking models indicate that these compounds, labeled compound 1 and compound 2, contact the conserved active sites (Cys144, Glu165, Gln191) of 3CL pro via hydrogen bonds. These findings provide insight into the antiviral activities of compounds 1 and 2 that may facilitate future research on anti-CoV drugs.

show abstract

Structural basis for the dimerization and substrate recognition specificity of porcine epidemic diarrhea virus 3C-like protease

Cited by 45 publications

References 51 publications

Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

Identification of two antiviral inhibitors targeting 3C-like serine/3C-like protease of porcine reproductive and respiratory syndrome virus and porcine epidemic diarrhea virus

What coronavirus 3C‐like protease tells us: From structure, substrate selectivity, to inhibitor design

Two Inhibitors Against the 3C-Like Proteases of Swine Coronavirus and Feline Coronavirus

Contact Info

Product

Resources

About