title: Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, IL 60612-7231, USA.
authors.forename: Marton
authors.initials: M
authors.lastname: Siklos
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, IL 60612-7231, USA.
authors.forename: Manel
authors.initials: M
authors.lastname: BenAissa
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, IL 60612-7231, USA.
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
keywords: 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