Caspases: Structure-Guided Design of Drugs to Control Cell Death

Weber, Irene T.; Fang, Bin; Agniswamy, Johnson

doi:10.2174/138955708785909899

Cited by 14 publications

(8 citation statements)

References 64 publications

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“…Compound IDN-6556 is one such example [43]. Although the structure of its complex with caspase is not available, the aromatic moiety at its N terminus is likely to bind in the S4 of caspase-3 [44]. This oxamyl peptide compound showed inhibition of all caspases and is currently under phase II clinical trials in patients with liver transplants [45].…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling

Fang

Agniswamy

et al. 2009

Apoptosis

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Caspase-3 recognition of various P4 residues in its numerous protein substrates was investigated by crystallography, kinetics, and calculations on model complexes. Asp is the most frequent P4 residue in peptide substrates, although a wide variety of P4 residues are found in the cellular proteins cleaved by caspase-3. The binding of peptidic inhibitors with hydrophobic P4 residues, or no P4 residue, is illustrated by crystal structures of caspase-3 complexes with Ac-IEPD-Cho, Ac-WEHD-Cho, Ac-YVAD-Cho, and Boc-D(OMe)-Fmk at resolutions of 1.9-2.6 A. The P4 residues formed favorable hydrophobic interactions in two separate hydrophobic regions of the binding site. The side chains of P4 Ile and Tyr form hydrophobic interactions with caspase-3 residues Trp206 and Trp214 within a non-polar pocket of the S4 subsite, while P4 Trp interacts with Phe250 and Phe252 that can also form the S5 subsite. These interactions of hydrophobic P4 residues are distinct from those for polar P4 Asp, which indicates the adaptability of caspase-3 for binding diverse P4 residues. The predicted trends in peptide binding from molecular models had high correlation with experimental values for peptide inhibitors. Analysis of structural models for the binding of 20 different amino acids at P4 in the aldehyde peptide Ac-XEVD-Cho suggested that the majority of hydrophilic P4 residues interact with Phe250, while hydrophobic residues interact with Trp206, Phe250, and Trp214. Overall, the S4 pocket of caspase-3 exhibits flexible adaptation for different residues and the new structures and models, especially for hydrophobic P4 residues, will be helpful for the design of caspase-3 based drugs.

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Section: Discussionmentioning

confidence: 99%

Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling

Fang

Agniswamy

et al. 2009

Apoptosis

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“…Caspases belong to a family of highly conserved cysteine-dependent aspartate-specific acid proteases that use a cysteine residue as catalytic nucleophile and share a stringent specificity for cleaving their substrates after aspartic acid residues in target proteins [11]. They are synthesized as inert zymogens and upon receipt of apoptotic stimuli, cells activate initiator caspases such as, caspase-1, -2, -8, -9, and -10 that, in turn, proteolytically cleave and activate effector caspases including caspase-3, -6, and -7 [12]. Caspases have been further categorized as either proinflammatory or proapoptotic, depending upon their participation in these cellular responses.…”

Section: Introductionmentioning

confidence: 99%

Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model

et al. 2014

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Background/Aims Hepatocyte cell death is a key feature of nonalcoholic steohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis. Methods C57BL/6 wild-type (WT), and caspase 3 knock out (Casp3−/−) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis were analyzed. Results WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3−/− fed the MCD diet showed similar serum ALT levels and NAFLD activity scores (NAS) compared to WT MCD-fed mice. However Casp3−/− mice on the MCD diet showed a marked reduction in expression of transcripts for pro-fibrogenic genes i which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3−/− mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes. Conclusion These findings support a prominent role for hepatocyte caspase 3 activation in NASH related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2 dependent infiltration of Ly6c positive monocytes.

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“…Caspases have been further categorized as either proinflammatory or proapoptotic, depending upon their participation in these cellular programs. The proinflammatory caspases include caspase 1, 11 and 12 in mouse and caspase 1, 4, and 5 in human (16). Targeting caspase activity and apoptosis has gained significant attention for developing of novel therapeutic diagnostic strategies for NASH patients.…”

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confidence: 99%

Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis

Dixon

Berk

Thapaliya

et al. 2012

Laboratory Investigation

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Nonalcoholic steatohepatitis (NASH) is typically associated with pro-apoptotic caspase activation. A potential role for pro-inflammatory caspases remains incompletely understood. Our aims were to examine a potential role of caspase 1 in the development of liver damage and fibrosis in NASH. C57BL/6 wild-type (WT), developed marked steatohepatitis, HSC activation, fibrosis, and increased hepatic caspase 1 and IL-1β expression when placed on the methioninecholine deficient (MCD) diet. Marked caspase 1 activation was detected in the liver of MCD-fed mice. Hepatocyte and non-parenchymal fractionation of the livers further demonstrated that caspase 1 activation after MCD feeding was mainly localized to non-parenchymal cells. Caspase 1-knockout (Casp1−/−) mice on the MCD diet showed marked reduction in mRNA expression of genes involved in inflammation and fibrogenesis (TNFα was 7.6-fold greater in WT vs. Casp1−/−MCD-fed mice; F4/80 was 1.5-fold greater in WT vs. Casp1−/− MCD-fed mice; α-SMA was 3.2-fold greater in WT vs. Casp1−/− MCD-fed mice; Collagen 1-alpha was 7.6–fold greater in WT vs. Casp1−/− MCD-fed mice; TGFβ was 2.4-fold greater in WT vs. Casp1−/− MCD-fed mice; CRP2 was 3.2-fold greater in WT vs. Casp1−/− MCD-fed mice). Furthermore, Sirius red staining for hepatic collagen deposition was significantly reduced in Casp1−/− mice MCD-fed mice compared to WT MCD-fed animals. However, serum aminotransferase (ALT) levels, caspase 3 activity and TUNEL positive cells were similar in Casp1−/− and WT mice on the MCD diet. Selective Kupffer cell depletion by clodronate injection markedly suppressed MCD-induced caspase 1 activation and protected mice from fibrogenesis and fibrosis associated with this diet. Conclusion: this study uncovers a novel role for caspase 1 in inflammation and fibrosis during NASH development.

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Caspases: Structure-Guided Design of Drugs to Control Cell Death

Cited by 14 publications

References 64 publications

Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling

Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling

Caspase 3 Inactivation Protects Against Hepatic Cell Death and Ameliorates Fibrogenesis in a Diet-Induced NASH Model

Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis

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