Synthesis of P1 aspartate-based peptide acyloxymethyl and fluoromethyl ketones as inhibitors of interleukin-1β-converting enzyme

Révész, Láśzló; Briswalter, Chantal; Heng, Richard; Leutwiler, Albert; Mueller, Rudolf; Wuethrich, H. J.

doi:10.1016/0040-4039(94)88361-0

Cited by 42 publications

(20 citation statements)

References 8 publications

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“…2C). Interestingly, NGF-induced DNA laddering (30 nM NGF for 24 hr) could be prevented by preincubation for 1 hr with the caspase inhibitor (Revesz et al, 1994) z-VAD-fmk (Fig. 2C).…”

Section: Ngf-induced Cell Death In Sk-n-mc Cellsmentioning

confidence: 91%

NGF induces apoptosis in a human neuroblastoma cell line expressing the neurotrophin receptor p75NTR

Kuner

Hertel

1998

J. Neurosci. Res.

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Nerve growth factor (NGF) has been demonstrated to support survival and differentiation of neuronal cells. Recently, a role of NGF in neuronal apoptosis has been suggested. NGF binds to tropomyosin receptor kinase A (TrkA) and to 75-kDa NGF receptor (p75NTR). TrkA is responsible for differentiation and survival, but p75NTR, a member of the death receptor family, seems to mediate the apoptotic effect of NGF. Here we demonstrate that NGF-but not neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF)-induced apoptosis in p75NTR-expressing human neuroblastoma SK-N-MC cells. BDNF prevented NGF-induced apoptosis. NGF-induced apoptosis was accompanied by the release of NFkappaB p65 and the activation of stress-activated protein kinase/c-jun amino terminal kinase. Because p75NTR and NGF are upregulated in Alzheimer's disease, NGF/p75NTR might be involved in neuronal cell death related to the disease.

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“…2C). Interestingly, NGF-induced DNA laddering (30 nM NGF for 24 hr) could be prevented by preincubation for 1 hr with the caspase inhibitor (Revesz et al, 1994) z-VAD-fmk (Fig. 2C).…”

Section: Ngf-induced Cell Death In Sk-n-mc Cellsmentioning

confidence: 91%

NGF induces apoptosis in a human neuroblastoma cell line expressing the neurotrophin receptor p75NTR

Kuner

Hertel

1998

J. Neurosci. Res.

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“…CBZ-ValLys(biotin)Asp-CH 2 F [ZVK(biotin)D-fmk] was prepared via a modified Pfitzer-Moffatt oxidation of CBZ-ValLys(biotin)NHCH(CH 2 CO 2 But)CH(OH)CH 2 F with EDAC and pyridinium trifluoroacetate in DMSO-CH 2 Cl 2 followed by deprotection with 35% TFA in CH 2 Cl 2 / anisole. The requisite alcohol was prepared by coupling CBZ-ValLys(biotin)-OH to H 2 NCH(CH 2 CO 2 Bu t )CH(OH)CH 2 F (Revesz et al, 1994) with EDAC-HOBt in DMF. CBZ-ValLys(biotin)-OH was prepared in three steps from CBZ-ValLys(Boc)-OMe by successive reactions with (1) 25% TFA in CH 2 Cl 2 , (2) D-biotin-OSu in CH 2 Cl 2 -DMF, and (3) 1.0 N NaOH in MeOH 2 0 (4:1).…”

Section: Methodsmentioning

confidence: 99%

Activation of the CED3/ICE-Related Protease CPP32 in Cerebellar Granule Neurons Undergoing Apoptosis But Not Necrosis

Armstrong¹,

Aja²,

Hoang³

et al. 1997

J. Neurosci.

271

195

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Neuronal apoptosis occurs during nervous system development and after pathological insults to the adult nervous system. Inhibition of CED3/ICE-related proteases has been shown to inhibit neuronal apoptosis in vitro and in vivo, indicating a role for these cysteine proteases in neuronal apoptosis. We have studied the activation of the CED3/ICE-related protease CPP32 in two in vitro models of mouse cerebellar granule neuronal cell death: K+/serum deprivation-induced apoptosis and glutamate-induced necrosis. Pretreatment of granule neurons with a selective, irreversible inhibitor of CED3/ICE family proteases, ZVAD-fluoromethylketone, specifically inhibited granule neuron apoptosis but not necrosis, indicating a selective role for CED3/ICE proteases in granule neuron apoptosis. Extracts prepared from apoptotic, but not necrotic, granule neurons contained a protease activity that cleaved the CPP32 substrate Ac-DEVD-aminomethylcoumarin. Induction of the protease activity was prevented by inhibitors of RNA or protein synthesis or by the CED3/ICE protease inhibitor. Affinity labeling of the protease activity with an irreversible CED3/ICE protease inhibitor, ZVK(biotin)D-fluoromethylketone, identified two putative protease subunits, p20 and p18, that were present in apoptotic but not necrotic granule neuron extracts. Western blotting with antibodies to the C terminus of the large subunit of mouse CPP32 (anti-CPP32) identified p20 and p18 as processed subunits of the CPP32 proenzyme. Anti-CPP32 specifically inhibited the DEVD-amc cleaving activity, verifying the presence of active CPP32 protease in the apoptotic granule neuron extracts. Western blotting demonstrated that the CPP32 proenzyme was expressed in granule neurons before induction of apoptosis. These results demonstrate that the CED3/ICE homolog CPP32 is processed and activated during cerebellar granule neuron apoptosis. CPP32 activation requires macromolecular synthesis and CED3/ICE protease activity. The lack of CPP32 activation during granule neuron necrosis suggests that proteolytic processing and activation of CED3/ICE proteases are specific biochemical markers of apoptosis.

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“…Protease Inhibitors and Substrates-ZVAD-FMK was synthesized as described (37). ZFA-FMK was purchased from Enzyme Systems Products (Dublin, CA).…”

Section: Methodsmentioning

confidence: 99%

Fas-induced Activation of the Cell Death-related Protease CPP32 Is Inhibited by Bcl-2 and by ICE Family Protease Inhibitors

Armstrong¹,

Aja²,

Xiang

et al. 1996

Journal of Biological Chemistry

293

214

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The human proto-oncogene bcl-2 and its Caenorhabditis elegans homologue ced-9 inhibit programmed cell death. In contrast, members of the human interleukin-1beta converting enzyme (ICE) family of cysteine proteases and their C. elegans homologue CED-3 promote the death program. Genetic experiments in C. elegans have shown that ced-9 is formally a negative regulator of ced-3 function, but neither those studies nor others have determined whether CED-9 or Bcl-2 proteins act biochemically upstream or downstream of CED-3/ICE proteases. CPP32, like all known members of the CED-3/ICE family, is synthesized as a proenzyme that is subsequently processed into an active protease with specificity for cleavage at Asp-X peptide bonds. In this report, we demonstrate that the CPP32 proenzyme is proteolytically processed and activated in Jurkat cells induced to die by Fas ligation. CPP32 activation is blocked by cell-permeable inhibitors of aspartate-directed, cysteine proteases, suggesting that pro-CPP32 is cleaved by active CPP32 or by other ICE family members. Heterologous expression of Bcl-2 in Jurkat cells prevents Fas-induced cell death as well as proteolytic processing and activation of CPP32. Thus, Bcl-2 acts at or upstream of the CPP32 activation step to inhibit apoptosis induced by Fas stimulation.

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Synthesis of P1 aspartate-based peptide acyloxymethyl and fluoromethyl ketones as inhibitors of interleukin-1β-converting enzyme

Cited by 42 publications

References 8 publications

NGF induces apoptosis in a human neuroblastoma cell line expressing the neurotrophin receptor p75NTR

NGF induces apoptosis in a human neuroblastoma cell line expressing the neurotrophin receptor p75NTR

Activation of the CED3/ICE-Related Protease CPP32 in Cerebellar Granule Neurons Undergoing Apoptosis But Not Necrosis

Fas-induced Activation of the Cell Death-related Protease CPP32 Is Inhibited by Bcl-2 and by ICE Family Protease Inhibitors

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