Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT57ID8)

• DTT Name: Respiratory syncytial virus protein F (RSV F)
• Synonyms: Protein F; Fusion glycoprotein F1; Fusion glycoprotein F0; F
• Gene Name: RSV F
• DTT Type: Successful target; [1]
• Related Disease:
  Low bone mass disorder [ICD-11: FB83]
  Viral encephalitis [ICD-11: 1C80]
• UniProt ID: FUS_HRSVA
• TTD ID: T07485
• Sequence:
  MELLILKANAITTILTAVTFCFASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIE
  LSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQSTPPTNNRARRELPRFMNYTLN
  NAKKTNVTLSKKRKRRFLGFLLGVGSAIASGVAVSKVLHLEGEVNKIKSALLSTNKAVVS
  LSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSCSISNIETVIEFQQKNNRLLEITREFSVN
  AGVTTPVSTYMLTNSELLSLINDMPITNDQKKLMSNNVQIVRQQSYSIMSIIKEEVLAYV
  VQLPLYGVIDTPCWKLHTSPLCTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKV
  QSNRVFCDTMNSLTLPSEINLCNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKT
  KCTASNKNRGIIKTFSNGCDYVSNKGMDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDP
  LVFPSDEFDASISQVNEKINQSLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLS
  LIAVGLLLYCKARSTPVTLSKDQLSGINNIAFSN
• Function: Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C- terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53- dependent apoptosis.

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lasofoxifene	DMHA18P	Osteoporosis	FB83.0	Approved	[2]
Palivizumab	DMQM9S0	Respiratory syncytial virus infection	1C80	Approved	[1]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Motavizumab	DMB24H7	Respiratory syncytial virus infection	1C80	Phase 3	[3]
SAR438584	DMDMAE4	Respiratory syncytial virus infection	1C80	Phase 3	[4]
MK-1654	DM2YNMI	Respiratory syncytial virus infection	1C80	Phase 2/3	[5]
GS-5806	DMDAHL6	Respiratory syncytial virus infection	1C80	Phase 2	[6]
JNJ-53718678	DMJ1FXL	Respiratory syncytial virus infection	1C80	Phase 2	[7]
RV521	DMSW5XJ	Respiratory syncytial virus infection	1C80	Phase 2	[8]
MEDI-557	DM6ADMG	Respiratory syncytial virus infection	1C80	Phase 1	[3]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TMC-353121	DMDSJO8	Respiratory syncytial virus infection	1C80	Preclinical	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CL-387626	DMA4DNX	Virus infection	1A24-1D9Z	Terminated	[9]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection. Curr Opin Drug Discov Devel. 2009 Jul;12(4):479-87.
• [3] Motavizumab. Correction in: MAbs. 2010 Sep-Oct; 2(5): 591.
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040470)
• [5] A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein. Nat Commun. 2019 Sep 12;10(1):4153.
• [6] Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study. J Med Chem. 2015 Feb 26;58(4):1630-43.
• [7] Antiviral Activity of Oral JNJ-53718678 in Healthy Adult Volunteers Challenged With Respiratory Syncytial Virus: A Placebo-Controlled Study. J Infect Dis. 2018 Jul 24;218(5):748-756.
• [8] Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion. J Med Chem. 2021 Apr 8;64(7):3658-3676.
• [9] Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein. Viruses. 2013 January; 5(1): 211-225.