Target Information
Target General Information | Top | |||||
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Target ID |
T07485
(Former ID: TTDI01919)
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Target Name |
Respiratory syncytial virus protein F (RSV F)
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Synonyms |
Protein F; Fusion glycoprotein F1; Fusion glycoprotein F0; F
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Gene Name |
RSV F
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Low bone mass disorder [ICD-11: FB83] | |||||
2 | Viral encephalitis [ICD-11: 1C80] | |||||
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.
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UniProt ID | ||||||
Sequence |
MELLILKANAITTILTAVTFCFASGQNITEEFYQSTCSAVSKGYLSALRTGWYTSVITIE
LSNIKENKCNGTDAKVKLIKQELDKYKNAVTELQLLMQSTPPTNNRARRELPRFMNYTLN NAKKTNVTLSKKRKRRFLGFLLGVGSAIASGVAVSKVLHLEGEVNKIKSALLSTNKAVVS LSNGVSVLTSKVLDLKNYIDKQLLPIVNKQSCSISNIETVIEFQQKNNRLLEITREFSVN AGVTTPVSTYMLTNSELLSLINDMPITNDQKKLMSNNVQIVRQQSYSIMSIIKEEVLAYV VQLPLYGVIDTPCWKLHTSPLCTTNTKEGSNICLTRTDRGWYCDNAGSVSFFPQAETCKV QSNRVFCDTMNSLTLPSEINLCNVDIFNPKYDCKIMTSKTDVSSSVITSLGAIVSCYGKT KCTASNKNRGIIKTFSNGCDYVSNKGMDTVSVGNTLYYVNKQEGKSLYVKGEPIINFYDP LVFPSDEFDASISQVNEKINQSLAFIRKSDELLHNVNAGKSTTNIMITTIIIVIIVILLS LIAVGLLLYCKARSTPVTLSKDQLSGINNIAFSN Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
1 | Lasofoxifene | Drug Info | Approved | Osteoporosis | [2], [3] | |
2 | Palivizumab | Drug Info | Approved | Respiratory syncytial virus infection | [4] | |
Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
1 | Motavizumab | Drug Info | Phase 3 | Respiratory syncytial virus infection | [5] | |
2 | SAR438584 | Drug Info | Phase 3 | Respiratory syncytial virus infection | [6] | |
3 | MK-1654 | Drug Info | Phase 2/3 | Respiratory syncytial virus infection | [7] | |
4 | GS-5806 | Drug Info | Phase 2 | Respiratory syncytial virus infection | [8] | |
5 | JNJ-53718678 | Drug Info | Phase 2 | Respiratory syncytial virus infection | [9] | |
6 | RV521 | Drug Info | Phase 2 | Respiratory syncytial virus infection | [10] | |
7 | MEDI-557 | Drug Info | Phase 1 | Respiratory syncytial virus infection | [11] | |
Preclinical Drug(s) | [+] 1 Preclinical Drugs | + | ||||
1 | TMC-353121 | Drug Info | Preclinical | Respiratory syncytial virus infection | [12] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | CL-387626 | Drug Info | Terminated | Virus infection | [13] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | Lasofoxifene | Drug Info | [14] | |||
2 | Palivizumab | Drug Info | [1] | |||
3 | Motavizumab | Drug Info | [15] | |||
Inhibitor | [+] 6 Inhibitor drugs | + | ||||
1 | MK-1654 | Drug Info | [17] | |||
2 | GS-5806 | Drug Info | [18] | |||
3 | JNJ-53718678 | Drug Info | [19] | |||
4 | RV521 | Drug Info | [20] | |||
5 | TMC-353121 | Drug Info | [14] | |||
6 | CL-387626 | Drug Info | [21] |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: TMC-353121 | Ligand Info | |||||
Structure Description | Solution structure of the respiratory syncytial virus (RSV)six-helix bundle complexed with TMC353121, a small-moleucule inhibitor of RSV | PDB:3KPE | ||||
Method | X-ray diffraction | Resolution | 1.47 Å | Mutation | No | [22] |
PDB Sequence |
> Chain A
HLEGEVNKIK 168 SALLSTNKAV178 VSLSNGVSVL188 TSKVLDLKNY198 IDKQLLPIV> Chain B FPSDEFDASI 492 SQVNEKINQS502 LAFIRKSDEL512 LHNVN
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Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
Ligand Name: BMS-433771 | Ligand Info | |||||
Structure Description | Crystal Structure of Inhibitor BMS-433771 in Complex with Prefusion RSV F Glycoprotein | PDB:5EA7 | ||||
Method | X-ray diffraction | Resolution | 2.85 Å | Mutation | Yes | [23] |
PDB Sequence |
NITEEFYQST
36 CSAVSKGYLS46 ALRTGWYTSV56 ITIELSNIAK75 VKLIKQELDK85 YKNAVTELQL 95 LMQFLGFLLG143 VGSAIASGVA153 VCKVLHLEGE163 VNKIKSALLS173 TNKAVVSLSN 183 GVSVLTFKVL193 DLKNYIDKQL203 LPILNSISNI217 ETVIEFQQKN227 NRLLEITREF 237 SVNAGVTTPV247 STYMLTNSEL257 LSLINDMPIT267 NDQKKLMSNN277 VQIVRQQSYS 287 IMCIIKEEVL297 AYVVQLPLYG307 VIDTPCWKLH317 TSPLCTTNTK327 EGSNICLTRT 337 DRGWYCDNAG347 SVSFFPQAET357 CKVQSNRVFC367 DTMNSLTLPS377 EVNLCNVDIF 387 NPKYDCKIMT397 SKTDVSSSVI407 TSLGAIVSCY417 GKTKCTASNK427 NRGIIKTFSN 437 GCDYVSNKGV447 DTVSVGNTLY457 YVNKQEGKSL467 YVKGEPIINF477 YDPLVFPSDE 487 FDASISQVNE497 KINQSLAFIR507 KSDEL
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Click to View More Binding Site Information of This Target with Different Ligands |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
References | Top | |||||
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REF 1 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. | |||||
REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7542). | |||||
REF 3 | Pfizer. Product Development Pipeline. March 31 2009. | |||||
REF 4 | Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. | |||||
REF 5 | ClinicalTrials.gov (NCT00129766) Study of MEDI-524 (Motavizumab) for the Prophylaxis of Serious Respiratory Syncytial Virus (RSV) Disease in High-Risk Children. U.S. National Institutes of Health. | |||||
REF 6 | ClinicalTrials.gov (NCT02325791) Study to Evaluate the Efficacy and Safety of REGN2222, for the Prevention of Medically Attended RSV (Respiratory Syncytial Virus) Infection in Preterm Infants. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT04767373) Efficacy and Safety of MK-1654 in Infants (MK-1654-004). U.S. National Institutes of Health. | |||||
REF 8 | ClinicalTrials.gov (NCT02135614) Efficacy, Pharmacokinetics, and Safety of GS-5806 in Hospitalized Adults With Respiratory Syncytial Virus (RSV) Infection. U.S. National Institutes of Health. | |||||
REF 9 | ClinicalTrials.gov (NCT04056611) Effects of JNJ-53718678 in Adult and Adolescent Participants Who Had a Hematopoietic Stem Cell Transplantation and Who Are Infected With Respiratory Syncytial Virus (RSV) (FREESIA). U.S. National Institutes of Health. | |||||
REF 10 | ClinicalTrials.gov (NCT03258502) Safety, Pharmacokinetics and Antiviral Activity of RV521 Against RSV. U.S. National Institutes of Health. | |||||
REF 11 | ClinicalTrials.gov (NCT01562938) MEDI-557 Adult Dosing. U.S. National Institutes of Health. | |||||
REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027151) | |||||
REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013835) | |||||
REF 14 | 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. | |||||
REF 15 | Motavizumab. Correction in: MAbs. 2010 Sep-Oct; 2(5): 591. | |||||
REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040470) | |||||
REF 17 | A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein. Nat Commun. 2019 Sep 12;10(1):4153. | |||||
REF 18 | 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. | |||||
REF 19 | 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. | |||||
REF 20 | Discovery of Sisunatovir (RV521), an Inhibitor of Respiratory Syncytial Virus Fusion. J Med Chem. 2021 Apr 8;64(7):3658-3676. | |||||
REF 21 | Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein. Viruses. 2013 January; 5(1): 211-225. | |||||
REF 22 | Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):308-13. | |||||
REF 23 | Molecular mechanism of respiratory syncytial virus fusion inhibitors. Nat Chem Biol. 2016 Feb;12(2):87-93. |
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