Cathepsin D—Managing the Delicate Balance
Abstract
:1. Introduction
2. Vital Functions of Cathepsin D
3. Cathepsin D Down-Regulation in Neurodegenerative Diseases
4. Treatment to Restore Cathepsin D
5. Excessive Levels of Cathepsin D in Neurodegenerative Disorders
6. Excessive Levels of Cathepsin D in Disorders Associated with Diabetes
7. Excessive Levels of Cathepsin D in Malignant Tumors
8. Cathepsin D Inhibitors
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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DNA 1 /Protein Change | Type of Mutation | Effect on Protease | NCL Type | Ref. |
---|---|---|---|---|
c.392A>G/p.Tyr131Cys | Missense | Reduced enzymatic activity | Late infantile NCL (LINCL) | [65] |
c.446G>T/p.Gly149Val | Missense | Reduced enzymatic activity | Juvenile NCL (JNCL) | [66] |
c.1196G>A/p.Arg399His | ||||
c.299C>T/p.Ser100Phe | Missense | Reduced enzymatic activity | Congenital CLN 2 (CLN10) | [67] |
c.764dupA/p.Tyr255 | Nonsense | Absence of protein | CLN10 | [56] |
c.6517T>A/p.Phe229Ile | Missense | Reduced protein amount and enzymatic activity | NCL-like disorder | [63] |
c.10267G>C/p.Trp383Cys |
Inhibitor | Mechanism | Ref. |
---|---|---|
Natural Compounds | ||
Pepstatin A from Actinomycetes | Non-competitive inhibitor | [141] |
Cycloheximide from Streptomyces griseus | Protein synthesis inhibitor | [142] |
The 22-kDa cathepsin D inhibitor protein of potatoes (PDI) from Solanum tuberosum | Reversible inhibitor | [143] |
Equistatin from Actinia equina | Reversible inhibitor | [144] |
Fucoidan from brown seaweeds and algae | Down-regulator of the expression | [126] |
Oxymatrine from Sophora flavescens | Down-regulator of the expression | [125] |
Morin hydrate from Maclura pomifera, Maclura tinctoria, Psidium guajava | Reversible inhibitor | [127] |
Synthetic compounds | ||
Dithiophosgene | Irreversible covalent inhibitor | [145] |
2,2-Dichloro-1,3-dithiacyclobutanone | ||
Diazo compounds | Irreversible covalent inhibitor | [146] |
Pro-Pro-Phe-Phe-Val-D-Leu | Reversible inhibitor | [147] |
Cbz-Val-Val-(3S4S)-statine | Reversible inhibitor | [148] |
Ibu-His-Pro-Phe-HCys-Sta-Leu-NH-[CH2]2-S-Acm | Reversible inhibitor | [149] |
Derivatives of 4-(morpholinylsulphonyl)-L-Phe-P2-(cyclohexyl)Ala psi[isostere]-P1′-P2′ | Irreversible covalent inhibitor | [150] |
Lentiviral shRNA constructs | RNA interference inhibitor | [76] |
Acylguanidines | Reversible inhibitor | [131,132] |
LY2811376 | Reversible inhibitor | [128] |
PtdIns(3)P 1 RNA aptamer | Inhibitor of PtdIns(3)P | [136] |
Macrocyclic inhibitors | Competitive inhibitor | [36] |
Necrostatin-1 | Suppressor of activity | [130] |
Polytherapy | ||
RL2 2, with chloroquine, Ku55933, and rapamycin from Streptomyces hygroscopicus | Suppressor of activity | [134] |
Praeruptorin C from Peucedanum praeruptorum and U0126 | Inhibitor through ERK1/2 3 signaling pathway | [133] |
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Mijanovic, O.; Petushkova, A.I.; Brankovic, A.; Turk, B.; Solovieva, A.B.; Nikitkina, A.I.; Bolevich, S.; Timashev, P.S.; Parodi, A.; Zamyatnin, A.A., Jr. Cathepsin D—Managing the Delicate Balance. Pharmaceutics 2021, 13, 837. https://doi.org/10.3390/pharmaceutics13060837
Mijanovic O, Petushkova AI, Brankovic A, Turk B, Solovieva AB, Nikitkina AI, Bolevich S, Timashev PS, Parodi A, Zamyatnin AA Jr. Cathepsin D—Managing the Delicate Balance. Pharmaceutics. 2021; 13(6):837. https://doi.org/10.3390/pharmaceutics13060837
Chicago/Turabian StyleMijanovic, Olja, Anastasiia I. Petushkova, Ana Brankovic, Boris Turk, Anna B. Solovieva, Angelina I. Nikitkina, Sergey Bolevich, Peter S. Timashev, Alessandro Parodi, and Andrey A. Zamyatnin, Jr. 2021. "Cathepsin D—Managing the Delicate Balance" Pharmaceutics 13, no. 6: 837. https://doi.org/10.3390/pharmaceutics13060837