Summary of probe development efforts to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)
Name: Summary of probe development efforts to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro) ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: Valerie Tokars and Andrew Mesecar, University of Illinois at Chicago (UIC)
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1-R03-MH084162-01A1
Grant Proposal PI: Valerie Tokars and Andrew Mesecar, UIC
External Assay ID: 3CLPRO_INH_LEADS_SUMMARY
Name: Summary of probe development efforts to identify inhibitors of the SARS coronavirus 3C-like Protease (3CLPro)
Coronaviruses are enveloped, large plus-strand RNA viruses that cause the common cold and other disorders such as lower respiratory tract infections and diarrhea (1). In 2003, the novel SARS coronavirus (SARS-CoV) was identified (2, 3) as the etiological agent of the global epidemic of severe acute respiratory syndrome (SARS), an atypical pneumonia that led to progressive respiratory failure in 8000 individuals and 800 deaths by July of that year (4). The SARS-CoV genome encodes a polypeptide that is proteolytically processed by two main proteases, one of which is the 3C-like protease (3CLpro). This chemotrypsin-like cysteine protease is essential for proteolytic processing of the coronavirus polyprotein and thus viral gene expression (5). The protein exists as a dimer/monomer mixture in solution and the dimer was confirmed to be the active species for the enzyme reaction (6). The current absence of a vaccine to prevent SARS infection, the possibility of future SARS epidemics, the recent cloning and expression of recombinant SARS 3CLpro (7), along with studies showing that 3CLpro is essential for viral life cycle, support a role for 3CL-pro as an important pathogenic component of SARS-CoV. The identification of specific inhibitors of 3CLpro will add insights into the biology of SARS-CoV infection of avian and mammalian cells, and serve as valuable tools for inhibiting SARS-CoV replication.
Summary of Probe Development Effort:
Following primary HTS in singlicate to identify 3CLPro inhibitors (AID1706), compounds were identified as possible candidates for probe development. A probe development effort is currently underway at the SRIMSC.
1. Myint, S.H., Human coronavirus infections, in The Coronaviridae, S.G. Siddell, Editor. 1995, Plenum Press. p. 389-401.
2. Ksiazek, T.G., Erdman, D., Goldsmith, C.S., Zaki, S.R., Peret, T., Emery, S., Tong, S., Urbani, C., Comer, J.A., Lim, W., Rollin, P.E., Dowell, S.F., Ling, A.E., Humphrey, C.D., Shieh, W.J., Guarner, J., Paddock, C.D., Rota, P., Fields, B., DeRisi, J., Yang, J.Y., Cox, N., Hughes, J.M., LeDuc, J.W., Bellini, W.J., and Anderson, L.J., A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med, 2003. 348(20): p. 1953-66
3. Drosten, C., Gunther, S., Preiser, W., van der Werf, S., Brodt, H.R., Becker, S., Rabenau, H., Panning, M., Kolesnikova, L., Fouchier, R.A., Berger, A., Burguiere, A.M., Cinatl, J., Eickmann, M., Escriou, N., Grywna, K., Kramme, S., Manuguerra, J.C., Muller, S., Rickerts, V., Sturmer, M., Vieth, S., Klenk, H.D., Osterhaus, A.D., Schmitz, H., and Doerr, H.W., Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med, 2003. 348(20): p. 1967-76.
4. Ziebuhr, J., Molecular biology of severe acute respiratory syndrome coronavirus. Curr Opin Microbiol, 2004. 7(4): p. 412-9.
5. Yang, H., Bartlam, M., and Rao, Z., Drug design targeting the main protease, the Achilles' heel of coronaviruses. Curr Pharm Des, 2006. 12(35): p. 4573-90.
6. Lai, L., Han, X., Chen, H., Wei, P., Huang, C., Liu, S., Fan, K., Zhou, L., Liu, Z., Pei, J., and Liu, Y., Quaternary structure, substrate selectivity and inhibitor design for SARS 3C-like proteinase. Curr Pharm Des, 2006. 12(35): p. 4555-64.
7. Fan, K., Wei, P., Feng, Q., Chen, S., Huang, C., Ma, L., Lai, B., Pei, J., Liu, Y., Chen, J., and Lai, L., Biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus 3C-like proteinase. J Biol Chem, 2004. 279(3): p. 1637-42.
Summary AID, 3CLpro, 3C-like protease, protease, cysteine protease, coronavirus, virus, SARS, SARS-CoV, primary screen, peptide cleavage, HTS, high throughput screen, 1536, inhibitor, QFRET, quenching fluorescence resonance energy transfer, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML188
PubChem Substance ID (SID) for probe 1: 99350510
PubChem Compound ID (CID) for probe 1: 46897844
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 1500
Disease relevance for probe 1: SARS
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133447/ (ID: 3025336)
Grant number for probe 1: MH084162-01A1
MLP Probe ML# for probe 2: ML300
PubChem Substance ID (SID) for probe 2: 99289112
PubChem Compound ID (CID) for probe 2: 69361347
Probe type for probe 2: Inhibitors
IC50/EC50 (nM) for probe 2: 1500
Target for probe 2: 3CLpro (gi: 73745819)
Disease relevance for probe 2: Coronaviruses
Anti-target for probe 2: none
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK143547/ (ID: 3036616)
Grant number for probe 2: MH084162-01A1
PubMed Publication ID (PMID) for probe 1: 23231439
PubMed Publication ID (PMID) for probe 2: 24080461
NCBI Book chapter title for probe 1: Discovery of non-covalent inhibitors of the SARS main proteinase 3CLpro
NCBI Book chapter title for probe 2: Non-covalent triazole-based inhibitors of the SARS main proteinase 3CLpro