Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTNHMO8)

• DTT Name: COVID-19 papain-like proteinase (PL-PRO)
• Synonyms: COVID-19 papain-like proteinase; COVID-19 PL2-PRO; COVID-19 PL-PRO; COVID-19 main proteinase; COVID-19 non-structural protein 3
• Gene Name: COVID-19 rep
• BioChemical Class: Coronaviruses polyprotein 1ab family
• UniProt ID: R1AB_SARS2 (819-2763)
• TTD ID: T87325
• EC Number: EC 3.4.19.12
• Sequence:
  APTKVTFGDDTVIEVQGYKSVNITFELDERIDKVLNEKCSAYTVELGTEVNEFACVVADA
  VIKTLQPVSELLTPLGIDLDEWSMATYYLFDESGEFKLASHMYCSFYPPDEDEEEGDCEE
  EEFEPSTQYEYGTEDDYQGKPLEFGATSAALQPEEEQEEDWLDDDSQQTVGQQDGSEDNQ
  TTTIQTIVEVQPQLEMELTPVVQTIEVNSFSGYLKLTDNVYIKNADIVEEAKKVKPTVVV
  NAANVYLKHGGGVAGALNKATNNAMQVESDDYIATNGPLKVGGSCVLSGHNLAKHCLHVV
  GPNVNKGEDIQLLKSAYENFNQHEVLLAPLLSAGIFGADPIHSLRVCVDTVRTNVYLAVF
  DKNLYDKLVSSFLEMKSEKQVEQKIAEIPKEEVKPFITESKPSVEQRKQDDKKIKACVEE
  VTTTLEETKFLTENLLLYIDINGNLHPDSATLVSDIDITFLKKDAPYIVGDVVQEGVLTA
  VVIPTKKAGGTTEMLAKALRKVPTDNYITTYPGQGLNGYTVEEAKTVLKKCKSAFYILPS
  IISNEKQEILGTVSWNLREMLAHAEETRKLMPVCVETKAIVSTIQRKYKGIKIQEGVVDY
  GARFYFYTSKTTVASLINTLNDLNETLVTMPLGYVTHGLNLEEAARYMRSLKVPATVSVS
  SPDAVTAYNGYLTSSSKTPEEHFIETISLAGSYKDWSYSGQSTQLGIEFLKRGDKSVYYT
  SNPTTFHLDGEVITFDNLKTLLSLREVRTIKVFTTVDNINLHTQVVDMSMTYGQQFGPTY
  LDGADVTKIKPHNSHEGKTFYVLPNDDTLRVEAFEYYHTTDPSFLGRYMSALNHTKKWKY
  PQVNGLTSIKWADNNCYLATALLTLQQIELKFNPPALQDAYYRARAGEAANFCALILAYC
  NKTVGELGDVRETMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQ
  FKKGVQIPCTCGKQATKYLVQQESPFVMMSAPPAQYELKHGTFTCASEYTGNYQCGHYKH
  ITSKETLYCIDGALLTKSSEYKGPITDVFYKENSYTTTIKPVTYKLDGVVCTEIDPKLDN
  YYKKDNSYFTEQPIDLVPNQPYPNASFDNFKFVCDNIKFADDLNQLTGYKKPASRELKVT
  FFPDLNGDVVAIDYKHYTPSFKKGAKLLHKPIVWHVNNATNKATYKPNTWCIRCLWSTKP
  VETSNSFDVLKSEDAQGMDNLACEDLKPVSEEVVENPTIQKDVLECNVKTTEVVGDIILK
  PANNSLKITEEVGHTDLMAAYVDNSSLTIKKPNELSRVLGLKTLATHGLAAVNSVPWDTI
  ANYAKPFLNKVVSTTTNIVTRCLNRVCTNYMPYFFTLLLQLCTFTRSTNSRIKASMPTTI
  AKNTVKSVGKFCLEASFNYLKSPNFSKLINIIIWFLLLSVCLGSLIYSTAALGVLMSNLG
  MPSYCTGYREGYLNSTNVTIATYCTGSIPCSVCLSGLDSLDTYPSLETIQITISSFKWDL
  TAFGLVAEWFLAYILFTRFFYVLGLAAIMQLFFSYFAVHFISNSWLMWLIINLVQMAPIS
  AMVRMYIFFASFYYVWKSYVHVVDGCNSSTCMMCYKRNRATRVECTTIVNGVRRSFYVYA
  NGGKGFCKLHNWNCVNCDTFCAGSTFISDEVARDLSLQFKRPINPTDQSSYIVDSVTVKN
  GSIHLYFDKAGQKTYERHSLSHFVNLDNLRANNTKGSLPINVIVFDGKSKCEESSAKSAS
  VYYSQLMCQPILLLDQALVSDVGDSAEVAVKMFDAYVNTFSSTFNVPMEKLKTLVATAEA
  ELAKNVSLDNVLSTFISAARQGFVDSDVETKDVVECLKLSHQSDIEVTGDSCNNYMLTYN
  KVENMTPRDLGACIDCSARHINAQVAKSHNIALIWNVKDFMSLSEQLRKQIRSAAKKNNL
  PF
• 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

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Disulfiram	DMCL2OK	Alcohol dependence	6C40.2	Approved	[1]
Isotretinoin	DM4QTBN	Acne vulgaris	ED80	Approved	[2]
SPI-1005	DM6XFHS	Reperfusion injury	ND56.Z	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PX-12	DMLVHAJ	Pancreatic cancer	2C10	Phase 2	[1]
Tideglusib	DME4LA1	Alzheimer disease	8A20	Phase 2	[1]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hexylcarbamoyl fluorouracil	DMYNPK8	Solid tumour/cancer	2A00-2F9Z	Withdrawn from market	[1]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GRL0617	DMX9AGF	Coronavirus infection	1D92	Preclinical	[3]

1 Preclinical Drugs Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID26868298-compound-N3	DMQFUCD	Middle East Respiratory Syndrome (MERS)	1D64	Preclinical	[1]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Isoarnebin 4	DM0B7NO	Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[1]

2 Investigative Agents Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID32321856-compound-11a	DMN39V6	Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]
PMID32321856-compound-11b	DM31QEY	Coronavirus Disease 2019 (COVID-19)	1D6Y	Investigative	[4]

References

• [1] Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9.
• [2] ClinicalTrials.gov (NCT04361422) Isotretinoin in Treatment of COVID-19. U.S. National Institutes of Health.
• [3] Crystal structure of SARS-CoV-2 papain-like protease. Acta Pharm Sin B. 2021 Jan;11(1):237-245.
• [4] Structure-based Design of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease. Science. 2020 Apr 22;eabb4489.