Sometimes Intermediates Do the Job!

Hilgenfeld, Rolf; Pumpor, Ksenia

doi:10.1016/j.chembiol.2006.03.002

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…In addition, a number of non‐peptidic, reversible inhibitors of the main protease have been discovered by virtual screening and/or docking on the basis of the crystal structure; examples for such compounds are cinanserin , arylboronic acids , isatin derivatives , selected diarylsulfones and a variety of others . Other non‐peptidic inhibitors, such as benzotriazole esters and non‐warheaded benzo triazoles , were discovered by screening of chemical libraries and subsequent optimization of the hits by medicinal chemistry. Chloropyridyl esters have been derived from the benzotriazole esters and found to have good antiviral activity in cell culture .…”

Section: Discovery and Design Of Mpro Inhibitorsmentioning

confidence: 99%

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

2014

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This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (M pro ) and the papain-like protease (PL pro ). The role of X-ray crystallography in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002-2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus M pro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PL pro and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus M pro s to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting.

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Section: Discovery and Design Of Mpro Inhibitorsmentioning

confidence: 99%

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

2014

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“…Left with few other options, physicians also tested HIV proteinase inhibitors (Stockman et al, 2006), and Wu et al (2006) found that one of them, lopinavir, targeted SARS-CoV M pro with an IC 50 of z50 mM. In their search for derivatives of lopinavir with an improved inhibitory action toward M pro , Wu et al (2006) noticed by serendipity that the intermediate benzotriazole esters occurring during the synthesis of these derivatives were better inhibitors of the enzyme than the final products (see also Hilgenfeld and Pumpor, 2006). These benzotriazole esters are the result of the activation of carboxylic acids by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), which was used as a coupling reagent in the synthesis of the lopinavir-like molecules.…”

Section: Introductionmentioning

confidence: 99%

A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters

Verschueren

Pumpor

Anemüller

et al. 2008

Chemistry & Biology

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The main proteinase (M(pro)) of the severe acute respiratory syndrome (SARS) coronavirus is a principal target for the design of anticoronaviral compounds. Benzotriazole esters have been reported as potent nonpeptidic inhibitors of the enzyme, but their exact mechanism of action remains unclear. Here we present crystal structures of SARS-CoV M(pro), the active-site cysteine of which has been acylated by benzotriazole esters that act as suicide inhibitors. In one of the structures, the thioester product has been hydrolyzed and benzoic acid is observed to bind to the hydrophobic S2 pocket. This structure also features the enzyme with a shortened N-terminal segment ("amputated N finger"). The results further the understanding of the important role of the N finger for catalysis as well as the design of benzotriazole inhibitors with improved specificity.

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“…The transition between the two conformations is believed to depend on the protonation/deprotonation of a histidine residue (His163) that interacts with the P1 glutamine residue of the substrate; this has been reproduced using molecular dynamics simulations [69 ]. Several structures of complexes with peptidomimetic inhibitors have been determined for the enzyme [66,71 ,72,73] and compounds that acylate the active site cysteine residue were also described as potent inhibitors [74,75]. Peptidyl aldehydes have been designed and synthesized as potentially reversible inhibitors [76].…”

Section: Replication: Nucleic Acid and Protein Synthesismentioning

confidence: 99%

Viral enzymes

Mesters

Tan

Hilgenfeld

2006

Current Opinion in Structural Biology

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Viral genomes show unequalled diversity, ranging from single-stranded DNA to double-stranded RNA. Moreover, viruses can quickly adapt to the host's immune response and drug treatment. Although they tend to make optimal use of the host cell's reservoir of proteins, viruses need to carry some enzymatic functions with them, as they may not be available or accessible in the infected cell. Recently, progress has been made in our structural understanding of viral enzymes involved in all stages of the viral life cycle, which includes entry, hijack, replication and exit stages.

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Sometimes Intermediates Do the Job!

Abstract: The SARS coronavirus main proteinase is a prime target for antiviral therapy. In this issue of Chemistry & Biology, Wu et al. describe potent inhibition of the enzyme by benzotriazole esters, which were originally obtained as intermediates in the synthesis of lopinavir derivatives .

Cited by 5 publications

References 11 publications

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

A Structural View of the Inactivation of the SARS Coronavirus Main Proteinase by Benzotriazole Esters

Viral enzymes

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