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Synthesis of Bioactive Peptides for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Jaison Jeevanandam, Ashish Kumar Solanki, Shailza Sharma, Prabir Kumar Kulabhusan, Sapna Pahil, Michael K. Danquah
The endoproteases enzymes possess the ability to catalyze and cleave terminal or penultimate peptide bond. They are further classified into amino and carboxypeptidases based on the cleavage of enzymes at amino or carboxy terminus. On the other hand, endoproteases are the enzymes that cleave the internal peptide bond. They are further classified based on the amino acids involved in catalytic mechanism which includes serine proteases, threonine proteases, cysteine proteases, metalloproteases, and aspartic proteases.
The proteasome as a target for protozoan parasites
Published in Expert Opinion on Therapeutic Targets, 2019
Stanley C. Xie, Lawrence R. Dick, Alexandra Gould, Stephen Brand, Leann Tilley
Peptide boronates, like peptide aldehydes, are covalent, slowly reversible inhibitors [26,38,39]. The two classes differ in that the boronic acid moiety is more metabolically stable than the aldehyde, and the peptide boronates are selective for serine and N-terminal threonine proteases. In contrast, peptide aldehydes can potently inhibit many cysteine proteases [40]. Peptide epoxyketones are irreversible, covalent inhibitors that react to form a unique morpholino ring system between the epoxyketone functional group and the N-terminal catalytic threonine, underpinning their specificity for the proteasome compared with other proteases [41]. Peptide vinyl sulfones are less reactive than epoxyketones and boronates for N-terminal threonine proteases (e.g. the proteasome). They are capable of a high degree of specificity, which can be exploited to decrease toxicity [42].
Design, synthesis, and in vitro evaluation of aza-peptide aldehydes and ketones as novel and selective protease inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Thomas S. Corrigan, Leilani M. Lotti Diaz, Sarah E. Border, Steven C. Ratigan, Kayla Q. Kasper, Daniel Sojka, Pavla Fajtova, Conor R. Caffrey, Guy S. Salvesen, Craig A. McElroy, Christopher M. Hadad, Özlem Doğan Ekici
The proteasome is a threonine protease and plays a central role in the ubiquitin-mediated degradation of unwanted proteins in the cell10. The proteasome is 750 kDa in molecular mass and has three active sites within its 20S catalytic core: chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L)11. Inhibition of the proteasome, which has been shown to be overexpressed in tumour cells12, leads to cellular apoptosis of the affected cells. Therefore, this inhibition strategy has been validated as an effective treatment for multiple myeloma patients13. Inhibitors, such as the aza-peptide aldehydes and ketones described here, are designed to cease proteolysis of mis-folded and unwanted proteins through the selective inhibition of the CT-L active site. Development of the proteasome inhibitor blockbuster drugs bortezomib (FDA-approved in 2003), carfilzomib14,15 (FDA-approved in 2012) and ixazomib (FDA-approved in 2015) revolutionised the treatment of multiple myeloma, significantly prolonging the lives of patients16. However, bortezomib shows severe side effects, such as peripheral neuropathy, in up to 64% of newly diagnosed multiple myeloma patients,17,18 largely due to off-target inhibition, by bortezomib’s boronic acid warhead19, of HtrA2/Omi, a serine protease involved in neuronal survival. Carfilzomib has been shown to result in less peripheral neuropathy, but lately it has been associated with adverse cardiovascular effects in up to 30% of the treated patients20. Ixazomib is an oral formulation and also possesses a boronic acid warhead; thus, peripheral neuropathy is still a major side effect. Therefore, careful dosing or discontinuation is also essential with ixazomib, as drug-induced peripheral neuropathy can be irreversible21. Hence, the search for new proteasome inhibitors is an ongoing challenge.