标签：
AD, Alzheimer?s disease ALS, amyotrophic lateral sclerosis APP, amyloid precursor protein APP/PS1, Aβ overexpressing mice APP (K670N/M671L) and PS1 (M146L) mutants Ala, alanine Alzheimer?s disease AppLon, London familial amyloid precursor protein mutation, APP (V717I) AppSwe, Swedish amyloid precursor protein mutation, APP (K670N/M671L) Arg, arginine Aβ, amyloid β Aβ1-42, amyloid β, 42 amino acid protein BACE-1, β-amyloid cleaving enzyme BBB, blood–brain barrier CANP, calcium-activated neutral protease CNS, central nervous system CREB, cyclic adenosine monophosphate response element binding protein CaMKII, Ca2+/calmodulin-dependent protein kinases II Calpain Cathepsin Cdk5/p35, activator of cyclin-dependent kinase 5 Cysteine protease DTT, dithioerythritol EGFR, epidermal growth factor receptor ERK1/2, extracellular signal-regulated kinase 1/2 Enzyme inhibitors GSH, glutathione Gln, glutamine Glu, glutamic acid Gly, glutamine Hsp70.1, heat shock protein 70.1 Ile, isoleucine KO, knockout Leu, leucine Lys, lysine MAP-2, microtubule-associated protein 2 MMP-9, matrix metalloproteinase 9 Met, methionine NFT, neurofibrilliary tangles Neurodegeneration Nle, norleucine PD, Parkinson?s disease PK, pharmacokinetic PKC, protein kinase C PTP1B, protein-tyrosine phosphatase 1B Phe, phenylalanine Pro, proline SP, senile plaques TBI, traumatic brain injury TNF, tumor necrosis factor Thr, threonine Tyr, tyrosine Val, valine WRX, Trp-Arg containing epoxysuccinate cysteine protease inhibitor WT, wildtype isoAsp, isoaspartate pGlu, pyroglutamate pyroGluAβ, pyroglutamate-amyloid β
Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
