| Structural highlights
Function
CASP3_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.[1] [2]
Publication Abstract from PubMed
Since the discovery of the caspase-2 (Casp2)-mediated âtau314 cleavage product and its associated impact on tauopathies such as Alzheimer's disease, the design of selective Casp2 inhibitors has become a focus in medicinal chemistry research. In the search for new lead structures with respect to Casp2 selectivity and drug-likeness, we have taken an approach by looking more closely at the specific sites of Casp2-mediated proteolysis. Using seven selected protein cleavage sequences, we synthesized a peptide series of 53 novel molecules and studied them using in vitro pharmacology, molecular modeling, and crystallography. Regarding Casp2 selectivity, AcITV(Dab)D-CHO (23) and AcITV(Dap)D-CHO (26) demonstrated the best selectivity (1-6-fold), although these trends were only moderate. However, some analogous tetrapeptides, most notably AcDKVD-CHO (45), showed significantly increased Casp3 selectivities (>100-fold). Tetra- and tripeptides display decreased or no Casp2 affinity, supporting the assumption that a motif of five amino acids is required for efficient Casp2 inhibition. Overall, the results provide a reasonable basis for the development of both selective Casp2 and Casp3 inhibitors.
Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis.,Bresinsky M, Strasser JM, Hubmann A, Vallaster B, McCue WM, Fuller J, Singh G, Nelson KM, Cuellar ME, Finzel BC, Ashe KH, Walters MA, Pockes S Arch Pharm (Weinheim). 2022 Sep;355(9):e2200095. doi: 10.1002/ardp.202200095. , Epub 2022 May 31. PMID:35642311[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:http://dx.doi.org/10.1038/376037a0
- ↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
- ↑ Bresinsky M, Strasser JM, Hubmann A, Vallaster B, McCue WM, Fuller J, Singh G, Nelson KM, Cuellar ME, Finzel BC, Ashe KH, Walters MA, Pockes S. Characterization of caspase-2 inhibitors based on specific sites of caspase-2-mediated proteolysis. Arch Pharm (Weinheim). 2022 Sep;355(9):e2200095. doi: 10.1002/ardp.202200095., Epub 2022 May 31. PMID:35642311 doi:http://dx.doi.org/10.1002/ardp.202200095
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