Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6275O)

• DTT Name: HRSV RNA-directed RNA polymerase L (HRSV L)
• Synonyms: Protein L; Large structural protein; Replicase; Transcriptase
• Gene Name: HRSV L
• DTT Type: Clinical trial target; [1]
• UniProt ID: L_HRSVA
• TTD ID: T45760
• Sequence:
  MDPIINGNSANVYLTDSYLKGVISFSECNALGSYIFNGPYLKNDYTNLISRQNPLIEHMN
  LKKLNITQSLISKYHKGEIKLEEPTYFQSLLMTYKSMTSSEQIATTNLLKKIIRRAIEIS
  DVKVYAILNKLGLKEKDKIKSNNGQDEDNSVITTIIKDDILSAVKDNQSHLKADKNHSTK
  QKDTIKTTLLKKLMCSMQHPPSWLIHWFNLYTKLNNILTQYRSNEVKNHGFTLIDNQTLS
  GFQFILNQYGCIVYHKELKRITVTTYNQFLTWKDISLSRLNVCLITWISNCLNTLNKSLG
  LRCGFNNVILTQLFLYGDCILKLFHNEGFYIIKEVEGFIMSLILNITEEDQFRKRFYNSM
  LNNITDAANKAQKNLLSRVCHTLLDKTVSDNIINGRWIILLSKFLKLIKLAGDNNLNNLS
  ELYFLFRIFGHPMVDERQAMDAVKINCNETKFYLLSSLSMLRGAFIYRIIKGFVNNYNRW
  PTLRNAIVLPLRWLTYYKLNTYPSLLELTERDLIVLSGLRFYREFRLPKKVDLEMIINDK
  AISPPKNLIWTSFPRNYMPSHIQNYIEHEKLKFSESDKSRRVLEYYLRDNKFNECDLYNC
  VVNQSYLNNPNHVVSLTGKERELSVGRMFAMQPGMFRQVQILAEKMIAENILQFFPESLT
  RYGDLELQKILELKAGISNKSNRYNDNYNNYISKCSIITDLSKFNQAFRYETSCICSDVL
  DELHGVQSLFSWLHLTIPHVTIICTYRHAPPYIGDHIVDLNNVDEQSGLYRYHMGGIEGW
  CQKLWTIEAISLLDLISLKGKFSITALINGDNQSIDISKPIRLMEGQTHAQADYLLALNS
  LKLLYKEYAGIGHKLKGTETYISRDMQFMSKTIQHNGVYYPASIKKVLRVGPWINTILDD
  FKVSLESIGSLTQELEYRGESLLCSLIFRNVWLYNQIALQLKNHALCNNKLYLDILKVLK
  HLKTFFNLDNIDTALTLYMNLPMLFGGGDPNLLYRSFYRRTPDFLTEAIVHSVFILSYYT
  NHDLKDKLQDLSDDRLNKFLTCIITFDKNPNAEFVTLMRDPQALGSERQAKITSEINRLA
  VTEVLSTAPNKIFSKSAQHYTTTEIDLNDIMQNIEPTYPHGLRVVYESLPFYKAEKIVNL
  ISGTKSITNILEKTSAIDLTDIDRATEMMRKNITLLIRILPLDCNRDKREILSMENLSIT
  ELSKYVRERSWSLSNIVGVTSPSIMYTMDIKYTTSTISSGIIIEKYNVNSLTRGERGPTK
  PWVGSSTQEKKTMPVYNRQVLTKKQRDQIDLLAKLDWVYASIDNKDEFMEELSIGTLGLT
  YEKAKKLFPQYLSVNYLHRLTVSSRPCEFPASIPAYRTTNYHFDTSPINRILTEKYGDED
  IDIVFQNCISFGLSLMSVVEQFTNVCPNRIILIPKLNEIHLMKPPIFTGDVDIHKLKQVI
  QKQHMFLPDKISLTQYVELFLSNKTLKSGSHVNSNLILAHKISDYFHNTYILSTNLAGHW
  ILIIQLMKDSKGIFEKDWGEGYITDHMFINLKVFFNAYKTYLLCFHKGYGKAKLECDMNT
  SDLLCVLELIDSSYWKSMSKVFLEQKVIKYILSQDASLHRVKGCHSFKLWFLKRLNVAEF
  TVCPWVVNIDYHPTHMKAILTYIDLVRMGLINIDRIHIKNKHKFNDEFYTSNLFYINYNF
  SDNTHLLTKHIRIANSELENNYNKLYHPTPETLENILANPIKSNDKKTLNDYCIGKNVDS
  IMLPLLSNKKLIKSSAMIRTNYSKQDLYNLFPMVVIDRIIDHSGNTAKSNQLYTTTSHQI
  SLVHNSTSLYCMLPWHHINRFNFVFSSTGCKISIEYILKDLKIKDPNCIAFIGEGAGNLL
  LRTVVELHPDIRYIYRSLKDCNDHSLPIEFLRLYNGHINIDYGENLTIPATDATNNIHWS
  YLHIKFAEPISLFVCDAELSVTVNWSKIIIEWSKHVRKCKYCSSVNKCMLIVKYHAQDDI
  DFKLDNITILKTYVCLGSKLKGSEVYLVLTIGPANIFPVFNVVQNAKLILSRTKNFIMPK
  KADKESIDANIKSLIPFLCYPITKKGINTALSKLKSVVSGDILSYSIAGRNEVFSNKLIN
  HKHMNILKWFNHVLNFRSTELNYNHLYMVESTYPYLSELLNSLTTNELKKLIKITGSLLY
  NFHNE
• Function: Responsible for RNA synthesis (replicase and transcriptase), cap addition, and cap methylation. Performs also the polyadenylation of subgenomic mRNAs by a stuttering mechanism at a slipery stop site present at the end of viral genes. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N) (Probable). The viral polymerase binds to the genomic RNA at two differents sites in the 3' leader promoter thereby initiating either genome replication or mRNA transcription. In the transcription mode, the polymerase performs the sequential transcription of all mRNAs using a termination-reinitiation mechanism responding to gene start and gene end signals. Some polymerase disengage from the template at each gene junction, resulting in a decreasing abundance of transcripts from the 3' to the 5' end of the genome (Probable). The first gene is the most transcribed, and the last the least transcribed (Probable). Needs as cofactors the phosphoprotein for processivity and the M2-1 anti-termination protein. Polyribonucleotidyl transferase (PRNTase) adds the cap structure when the nascent RNA chain length has reached few nucleotides. Ribose 2'-O methylation of viral mRNA cap precedes and facilitates subsequent guanine-N-7 methylation (By similarity). In the replication mode, the polymerase replicates the whole viral genome without recognizing the gene end transcriptional signals. The ability of the polymerase to override the gene end signals as it is producing the antigenome is probably due to replicative RNA becoming encapsidated with nucleoprotein as it is synthesized.

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
JNJ-64417184	DMYJCUP	Respiratory syncytial virus infection	1C80	Phase 1	[1]

References

• [1] Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res. 2019 Jul;167:45-67.