Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease

Shao, Yi; Yang, Wen Bin; Kuo, Tun Hsun; Tsai, Keng‐Chang; Lin, Chun Hung; Yang, An‐Suei; Liang, Po‐Huang; Wong, Chi Huey

doi:10.1016/j.bmc.2008.02.040

Cited by 71 publications

(49 citation statements)

References 31 publications

(6 reference statements)

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“…While continuing to explore the SARs based on FMK inhibitors, a series of trifluoro methyl ketones 61−68 were developed, mainly focusing on the P1 and P2−P4 positions ( Table 6). 78 Three different amino acids were demonstrated as variable residues at positions P1−P4. The inhibitory activities were observed to range from 10 to 50 μM.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

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Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10-15%) fatalities in 2003. The causative agent of SARS has been identified as a novel human coronavirus (SARS-CoV), and its viral protease, SARS-CoV 3CL(pro), has been shown to be essential for replication and has hence been recognized as a potent drug target for SARS infection. Currently, there is no effective treatment for this epidemic despite the intensive research that has been undertaken since 2003 (over 3500 publications). This perspective focuses on the status of various efficacious anti-SARS-CoV 3CL(pro) chemotherapies discovered during the last 12 years (2003-2015) from all sources, including laboratory synthetic methods, natural products, and virtual screening. We describe here mainly peptidomimetic and small molecule inhibitors of SARS-CoV 3CL(pro). Attempts have been made to provide a complete description of the structural features and binding modes of these inhibitors under many conditions.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Perspective Inhibitor 61 showed time-dependent inhibition, with a K i value of 0.3 μM after a 4 h incubation. 78 4.7. Symmetric Peptides.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

et al. 2016

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“…Virtual screening (Plewczynski et al, 2007;Mukherjee et al, 2008;Nguyen et al, 2011) or a high-throughput screening of small molecule libraries have identified inhibitorsincluding an anti-HIV agent and serotonin antagonist, cinanserin (Blanchard et al, 2004;Kao et al, 2004;Wu et al, 2004a;Chen et al, 2005). Other 3CL protease inhibitors identified so far belongto categories such as plant derived phenolic or flavonoid compounds (Lin et al, 2005;Nguyen et al, 2012), active site, nonactive site or competitive inhibitors (Kaeppler et al, 2005;Lee et al, 2005;Du et al, 2007;Ryu et al, 2010), ketones or ester based inhibitors (Goetz et al, 2007;Zhang et al, 2007;Ghosh et al, 2008;Shao et al, 2008;Verschueren et al, 2008;Zhang et al, 2008), modified peptidomimetic inhibitors (Ghosh et al, 2007), metal conjugated inhibitors (Lee et al, 2007;…”

Section: Viral Protease Inhibitorsmentioning

confidence: 99%

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

Bhardwaj¹

2013

American Journal of Virology

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No non-human reservoirs for smallpox-and polio-viruses has contributed to the success of worldwide eradication of smallpox and a significant control of poliomyelitis. Most emerging and re-emerging viruses including SARS Coronavirus (SARS-CoV), have animal reservoirs and therefore,they impose a constant threat of host jump leading tooutbreaksin humans. It is desirable to be ready for control of infections that are caused by zoonotic pathogens, even after an outbreak has ended. This literature review is a compilation of advances made so far for diagnosis and treatment of SARS.

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“…Because 3CL pro is essential to viral replication and its active-site structure is conserved, the protease is an attractive drug target for the development of such a broadspectrum inhibitor [7]. The SARS-CoV 3CL pro can be inactivated by peptidomimetic inhibitors that are composed of a substrate-like peptide and a reactive warhead such as an aldehyde [8,9], a Michael acceptor [7,10,11], a halo-methyl ketone [10,12], or an epoxide [13]. The peptide interacts with the substrate-binding cleft of the protease to form a non-covalent complex, and then the warhead covalently links with the catalytic cysteine residue and inhibits the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases

Chuck

Chen

et al. 2013

European Journal of Medicinal Chemistry

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Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6-49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ~10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection.

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Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease

Cited by 71 publications

References 31 publications

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

An Overview of Severe Acute Respiratory Syndrome–Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases

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