Inhibitor of apoptosis
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The Inhibitors of apoptosis proteins (IAP) are a family of functionally and structurally related proteins that serve as endogenous inhibitors of programmed cell death (apoptosis). A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid domain) in one to three copies. The human IAP family consists of 8 members, and IAP homologs have been identified in numerous organisms.
The first members of the IAPs identified were from the baculovirus IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs were discovered which included XIAP, c-IAPl, C-IAP2, NAIP, Livin and Survivin.
The best characterized IAP is XIAP, which binds caspase-9, caspase-3 and caspase-7, thereby inhibiting their activation and preventing apoptosis. Also cIAP1 and cIAP2 have been shown to bind caspases, although how the IAPs inhibit apoptosis mechanistically at the molecular level is not completely understood.
Since the mid 2000s, significant progress has been made into the development of small molecule mimics of the endogenous IAP ligand Smac. One recent example published in 2013 describes the synthesis and testing of peptidomimetics whose structure is based on the AVPI tetrapeptide IAP binding motif present in the N-terminus of mature Smac. These peptidomimetic compounds were specifically noted for their exceptionally high level of binding to Livin, one of the important IAP family members yet to receive much attention from a drug discovery perspective.
- Vamos, Mitchell; Welsh, Kate; Finlay, Darren; Lee, Pooi San; Mace, Peter; Snipas, Scott; Gonzalez, Monica; Ganji, Santhi; Ardecky, Robert; Riedl, Stefan; Salvesen, Guy; Vuori, Kristiina; Reed, John; Cosford, Nicholas (2013). "Expedient Synthesis of Highly Potent Antagonists of Inhibitor of Apoptosis Proteins (IAPs) with Unique Selectivity for ML-IAP". ACS Chemical Biology 8: 725–732. doi:10.1021/cb3005512. PMID 23323685.
- The MEROPS online database for peptidases and their inhibitors: I32.002
- Inhibitor of Apoptosis Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)