Prospects for drug development of ubiquitin-specific protease 30 (USP30)

ubiquitin-specific protease(ubiquitin-specific processing peptidase, USPs)Attributable to deubiquitinating enzymes(Deubiquitinating enzymes, DUbs)Is a member of the protease superfamily, one of the isomers of cysteine protease, mainly acts on the ubiquitin proteasome system is ubiquitinated proteins, regulating cell growth and development, regulating cell cycle, regulating cell signal transduction and so on.

ubiquitin-specific protease30 (Ubquitin-specific protease 30, USP30)It is a member of the deubiquitinase family, mainly located in the outer membrane of mitochondria, and is a cysteine protease. Studies have shownUSP30involved in the regulation of mitochondrial morphology in cells, subsequent studies found thatUSP30can makePARK2andPINK1driven mitophagy is reversed,PARK2As ubiquitin ligase marks damaged mitochondria so that they are cleared, andUSP30As a deubiquitinating enzyme, it can remove ubiquitin tags and inhibit mitochondrial autophagy, inhibitUSP30It is also expected to be used to treat Parkinson's disease.

A number of companies have already started.USP30the development of inhibitors,KomanderHuman sources have been parsedUSP30The structure(PDB ID: 5OHK, 5OHN, 5OHP):USP30The most critical catalytic triad in the catalytic domainCys77-His452-Ser477, different fromUSPCommon in the family.Cys-His-Asp/AsnTriad.

DomesticUSP30Research Progress of Inhibitors

The Kunming Institute of Botany, Chinese Academy of Sciences, Hao Xiaojiang and others reported aUSP30Inhibitors: diterpene derivatives15-oxospyramilactone (S3)It is also the only natural product source.USP30inhibitors,S3can inhibit deubiquitination, thereby enhancing mitochondrial membrane proteinsMFfn1/2activity, promote mitochondrial fusion. It is worth noting that the patent declarationCN103360358BContent is based on15-oxospyramilactone (S3)derivativesWntApplication of signaling pathway inhibitors in the preparation of antitumor drugs.

of pharmaceutical companiesUSP30Progress in research and development of inhibitors

Mission Therapeuticsby the University of CambridgeSteve JacksonProfessor et al.2011Co-founded a pharmaceutical company dedicated to selectively targeting deubiquitinating enzymes with small molecule inhibitors (DUB), to effectively treat patients with serious and life-threatening diseases, the company is currently focusing onUSP4,USP7,USP30andUCHL1, in whichUSP30The inhibitor program focuses on mitochondrial-related diseases, Parkinson's disease, and peripheral diseases such as renal fibrosis.

Mission TherapeuticsAlso currentlyUSP30The absolute main force of the inhibitor research and development army has been publicly and.USP30There are dozens of related patents. It has been publicly reported in the patentUSP30Representative compounds of inhibitors, but the compounds reported by the company are not described in detail.IC₅₀and other key data, only a rough range of activity data.

Recently, another pharmaceutical companyForma TherapeuticsAlso disclosed one.USP30Patent application for inhibitorsWO2019071073A1. withMission TherapeuticsSimilarly, in its patentUSP30The inhibitory activity of is not given a specific value, only a rough range.

Conclusion

SP30As a member of the large family of deubiquitinase, the study of its biological mechanism is still not much, but because of its location in the mitochondria, this characteristic is bound to be inextricably linked with mitochondrial-related diseases. Currently, natural product sourcesUSP30Only one case has been reported, and subsequent progress is uncertain, while several pharmaceutical companies have reportedUSP30Inhibitor research is not deep enough,USP30The crystal structure of has been resolved, which will beUSP30The design of the inhibitor provides more convenience. WithUSP30The role in different diseases is becoming clearer,USP30The development of inhibitors could be likeUSP7The research and development of inhibitors has entered the fierce competition situation.

Reference: https://med.sina.com/article_detail_103_2_65170.html