Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTYJOLE)

• DTT Name: MERS-CoV papain-like proteinase (PL-PRO)
• Synonyms: MERS-CoV PLpro; MERS-CoV Non-structural protein 3; MERS-CoV nsp3
• Gene Name: MERS-CoV rep
• BioChemical Class: Coronaviruses polyprotein 1ab family
• UniProt ID: R1AB_CVEMC (854-2740)
• TTD ID: T18143
• EC Number: EC 3.4.19.12
• Sequence:
  APVKKVAFGGDQVHEVAAVRSVTVEYNIHAVLDTLLASSSLRTFVVDKSLSIEEFADVVK
  EQVSDLLVKLLRGMPIPDFDLDDFIDAPCYCFNAEGDASWSSTMIFSLHPVECDEECSEV
  EASDLEEGESECISETSTEQVDVSHEISDDEWAAAVDEAFPLDEAEDVTESVQEEAQPVE
  VPVEDIAQVVIADTLQETPVVSDTVEVPPQVVKLPSEPQTIQPEVKEVAPVYEADTEQTQ
  SVTVKPKRLRKKRNVDPLSNFEHKVITECVTIVLGDAIQVAKCYGESVLVNAANTHLKHG
  GGIAGAINAASKGAVQKESDEYILAKGPLQVGDSVLLQGHSLAKNILHVVGPDARAKQDV
  SLLSKCYKAMNAYPLVVTPLVSAGIFGVKPAVSFDYLIREAKTRVLVVVNSQDVYKSLTI
  VDIPQSLTFSYDGLRGAIRKAKDYGFTVFVCTDNSANTKVLRNKGVDYTKKFLTVDGVQY
  YCYTSKDTLDDILQQANKSVGIISMPLGYVSHGLDLIQAGSVVRRVNVPYVCLLANKEQE
  AILMSEDVKLNPSEDFIKHVRTNGGYNSWHLVEGELLVQDLRLNKLLHWSDQTICYKDSV
  FYVVKNSTAFPFETLSACRAYLDSRTTQQLTIEVLVTVDGVNFRTVVLNNKNTYRSQLGC
  VFFNGADISDTIPDEKQNGHSLYLADNLTADETKALKELYGPVDPTFLHRFYSLKAAVHK
  WKMVVCDKVRSLKLSDNNCYLNAVIMTLDLLKDIKFVIPALQHAFMKHKGGDSTDFIALI
  MAYGNCTFGAPDDASRLLHTVLAKAELCCSARMVWREWCNVCGIKDVVLQGLKACCYVGV
  QTVEDLRARMTYVCQCGGERHRQIVEHTTPWLLLSGTPNEKLVTTSTAPDFVAFNVFQGI
  ETAVGHYVHARLKGGLILKFDSGTVSKTSDWKCKVTDVLFPGQKYSSDCNVVRYSLDGNF
  RTEVDPDLSAFYVKDGKYFTSEPPVTYSPATILAGSVYTNSCLVSSDGQPGGDAISLSFN
  NLLGFDSSKPVTKKYTYSFLPKEDGDVLLAEFDTYDPIYKNGAMYKGKPILWVNKASYDT
  NLNKFNRASLRQIFDVAPIELENKFTPLSVESTPVEPPTVDVVALQQEMTIVKCKGLNKP
  FVKDNVSFVADDSGTPVVEYLSKEDLHTLYVDPKYQVIVLKDNVLSSMLRLHTVESGDIN
  VVAASGSLTRKVKLLFRASFYFKEFATRTFTATTAVGSCIKSVVRHLGVTKGILTGCFSF
  VKMLFMLPLAYFSDSKLGTTEVKVSALKTAGVVTGNVVKQCCTAAVDLSMDKLRRVDWKS
  TLRLLLMLCTTMVLLSSVYHLYVFNQVLSSDVMFEDAQGLKKFYKEVRAYLGISSACDGL
  ASAYRANSFDVPTFCANRSAMCNWCLISQDSITHYPALKMVQTHLSHYVLNIDWLWFAFE
  TGLAYMLYTSAFNWLLLAGTLHYFFAQTSIFVDWRSYNYAVSSAFWLFTHIPMAGLVRMY
  NLLACLWLLRKFYQHVINGCKDTACLLCYKRNRLTRVEASTVVCGGKRTFYITANGGISF
  CRRHNWNCVDCDTAGVGNTFICEEVANDLTTALRRPINATDRSHYYVDSVTVKETVVQFN
  YRRDGQPFYERFPLCAFTNLDKLKFKEVCKTTTGIPEYNFIIYDSSDRGQESLARSACVY
  YSQVLCKSILLVDSSLVTSVGDSSEIATKMFDSFVNSFVSLYNVTRDKLEKLISTARDGV
  RRGDNFHSVLTTFIDAARGPAGVESDVETNEIVDSVQYAHKHDIQITNESYNNYVPSYVK
  PDSVSTSDLGSLIDCNAASVNQIVLRNSNGACIWNAAAYMKLSDALKRQIRIACRKCNLA
  FRLTTSKLRANDNILSVRFTANKIVGG
• Function: Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Disulfiram	DMCL2OK	Alcohol dependence	6C40.2	Approved	[2]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[1]
Mycophenolic acid	DMRBMAU	Crohn disease	DD70	Approved	[3]
Thioguanine	DM7NKEV	Acute lymphocytic leukaemia	2B33.3	Approved	[1]

1 Preclinical Drugs Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID30940566-compound-6	DMXCKL9	Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[4]

References

• [1] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015 Mar;115:9-16.
• [2] Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020 Mar;19(3):149-150.
• [3] SARS and MERS: recent insights into emerging coronaviruses. Nat Rev Microbiol. 2016 Aug;14(8):523-34.
• [4] Identification and Design of Novel Small Molecule Inhibitors Against MERS-CoV Papain-Like Protease via High-Throughput Screening and Molecular Modeling Bioorg Med Chem. 2019 May 15;27(10):1981-1989.