Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis
Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protei...
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| Vydané v: | Journal of medicinal chemistry Ročník 47; číslo 10; s. 2466 |
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| Hlavní autori: | , , , , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
06.05.2004
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| ISSN: | 0022-2623 |
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| Abstract | Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency. |
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| AbstractList | Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency. Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency. |
| Author | Grimm, Erich Gallant, Michel Soisson, Stephen M Bayly, Christopher McKay, Dan Becker, Joseph W Rotonda, Jennifer Garcia-Calvo, Marga Francoeur, Sébastien Nicholson, Donald W Han, Yongxin Thornberry, Nancy Zamboni, Robert Peterson, Erin Aspiotis, Renee Giroux, Andre Renaud, Johanne Roy, Sophie |
| Author_xml | – sequence: 1 givenname: Joseph W surname: Becker fullname: Becker, Joseph W email: joseph_becker@merck.com organization: Departments of Medicinal Chemistry and Metabolic Disorders, Merck Research Laboratory, PO Box 2000, Rahway, New Jersey 07065, USA. joseph_becker@merck.com – sequence: 2 givenname: Jennifer surname: Rotonda fullname: Rotonda, Jennifer – sequence: 3 givenname: Stephen M surname: Soisson fullname: Soisson, Stephen M – sequence: 4 givenname: Renee surname: Aspiotis fullname: Aspiotis, Renee – sequence: 5 givenname: Christopher surname: Bayly fullname: Bayly, Christopher – sequence: 6 givenname: Sébastien surname: Francoeur fullname: Francoeur, Sébastien – sequence: 7 givenname: Michel surname: Gallant fullname: Gallant, Michel – sequence: 8 givenname: Marga surname: Garcia-Calvo fullname: Garcia-Calvo, Marga – sequence: 9 givenname: Andre surname: Giroux fullname: Giroux, Andre – sequence: 10 givenname: Erich surname: Grimm fullname: Grimm, Erich – sequence: 11 givenname: Yongxin surname: Han fullname: Han, Yongxin – sequence: 12 givenname: Dan surname: McKay fullname: McKay, Dan – sequence: 13 givenname: Donald W surname: Nicholson fullname: Nicholson, Donald W – sequence: 14 givenname: Erin surname: Peterson fullname: Peterson, Erin – sequence: 15 givenname: Johanne surname: Renaud fullname: Renaud, Johanne – sequence: 16 givenname: Sophie surname: Roy fullname: Roy, Sophie – sequence: 17 givenname: Nancy surname: Thornberry fullname: Thornberry, Nancy – sequence: 18 givenname: Robert surname: Zamboni fullname: Zamboni, Robert |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/15115390$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Caspase 3 Caspase Inhibitors Caspases - chemistry Crystallography, X-Ray Enzyme Inhibitors - chemistry Heterocyclic Compounds, 3-Ring - chemistry Ligands Models, Molecular Molecular Mimicry Molecular Structure Niacin - analogs & derivatives Niacin - chemistry Oligopeptides - chemistry Peptides - chemistry Protein Conformation Pyrazines - chemistry Structure-Activity Relationship |
| Title | Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis |
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