Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses.

The respiratory syncytial virus (RSV) fusion glycoprotein (F) can interact with the small intracellular GTPase RhoA, and peptides derived from RhoA inhibit RSV replication. These observations initially suggested that RhoA-derived peptides might inhibit RSV replication by disrupting an in vivo interaction between RSV F and RhoA. However, recent data indicate that the antiviral activity of RhoA-derived peptides is not due to competitive inhibition of an hypothesized F-RhoA interaction, but is rather a function of the peptides' intrinsic biophysical properties. We summarize here what is known about the mechanism of RSV inhibition by these peptides and give our opinion regarding the potential implications of this work with regards to RSV biology, and to the development of antiviral agents targeting RSV and other enveloped viruses.

[1]  K. M. Hwang,et al.  Synthetic CD4 peptide derivatives that inhibit HIV infection and cytopathicity. , 1988, Science.

[2]  M. Lüscher-mattli,et al.  Polyanions — A Lost Chance in the Fight against HIV and other Virus Diseases? , 2000, Antiviral chemistry & chemotherapy.

[3]  C. Richardson,et al.  Oligopeptides that specifically inhibit membrane fusion by paramyxoviruses: studies on the site of action. , 1983, Virology.

[4]  M. Vafina,et al.  CD4-derived peptide and sulfated polysaccharides have similar mechanisms of anti-HIV activity based on electrostatic interactions with positively charged gp120 fragments. , 1993, Molecular immunology.

[5]  J. Melero,et al.  Binding of human respiratory syncytial virus to cells: implication of sulfated cell surface proteoglycans. , 2000, The Journal of general virology.

[6]  Jian Liu,et al.  Cell surface heparan sulfate and its roles in assisting viral infections , 2002, Medicinal research reviews.

[7]  K. Ikuta,et al.  Characterization of a unique scrambled peptide derived from the CD4 CDR3-related region which shows substantial activity for blocking HIV-1 infection. , 1993, Vaccine.

[8]  J. Montaner,et al.  Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. , 2003, The New England journal of medicine.

[9]  J. Crowe,et al.  A RhoA-derived peptide inhibits syncytium formation induced by respiratory syncytial virus and parainfluenza virus type 3 , 2000, Nature Medicine.

[10]  K. M. Hwang,et al.  CD4(81-92)-based peptide derivatives. Structural requirements for blockade of HIV infection, blockade of HIV-induced syncytium formation, and virostatic activity in vitro. , 1992, Biochemical pharmacology.

[11]  D. Lambert,et al.  Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  B. Graham,et al.  RhoA-Derived Peptide Dimers Share Mechanistic Properties with Other Polyanionic Inhibitors of Respiratory Syncytial Virus (RSV), Including Disruption of Viral Attachment and Dependence on RSV G , 2004, Journal of Virology.

[13]  B. Graham,et al.  Antiviral Activity of RhoA-Derived Peptides against Respiratory Syncytial Virus Is Dependent on Formation of Peptide Dimers , 2003, Antimicrobial Agents and Chemotherapy.

[14]  N. Meanwell,et al.  Fundamental structure-activity relationships associated with a new structural class of respiratory syncytial virus inhibitor. , 2003, Bioorganic & medicinal chemistry letters.

[15]  P. Spear,et al.  Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. , 2001, The Journal of clinical investigation.

[16]  K. Ikuta,et al.  Increased anti‐HIV‐1 activity of CD4 CDR3‐related synthetic peptides by scrambling and further structural modifications, including d‐isomerization and dimerization , 1993, FEBS letters.

[17]  J. Sinnott,et al.  Respiratory Syncytial Virus , 1988, Infection Control & Hospital Epidemiology.

[18]  F. Robey,et al.  The V3 region of the envelope glycoprotein of human immunodeficiency virus type 1 binds sulfated polysaccharides and CD4-derived synthetic peptides. , 1992, The Journal of biological chemistry.

[19]  J. Sodroski,et al.  Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody , 1998, Nature.

[20]  S. Feldman,et al.  The Fusion Glycoprotein of Human Respiratory Syncytial Virus Facilitates Virus Attachment and Infectivity via an Interaction with Cellular Heparan Sulfate , 2000, Journal of Virology.

[21]  M. E. Lynch,et al.  Inhalation efficacy of RFI‐641 in an African green monkey model of RSV infection , 2003, Journal of medical primatology.

[22]  S. Shigeta,et al.  Recent progress in antiviral chemotherapy for respiratory syncytial virus infections , 2000, Expert opinion on investigational drugs.

[23]  J. Crowe,et al.  RhoA Interacts with the Fusion Glycoprotein of Respiratory Syncytial Virus and Facilitates Virus-Induced Syncytium Formation , 1999, Journal of Virology.

[24]  P. Collins,et al.  Iduronic acid-containing glycosaminoglycans on target cells are required for efficient respiratory syncytial virus infection. , 2000, Virology.

[25]  J. Sodroski,et al.  Selective Interactions of Polyanions with Basic Surfaces on Human Immunodeficiency Virus Type 1 gp120 , 2000, Journal of Virology.

[26]  D. Spillmann,et al.  Glycosaminoglycan Sulfation Requirements for Respiratory Syncytial Virus Infection , 2000, Journal of Virology.

[27]  K. Takahashi,et al.  Antiviral activity of NMSO3 against respiratory syncytial virus infection in vitro and in vivo. , 2000, Antiviral research.

[28]  G. Prince,et al.  An update on respiratory syncytial virus antiviral agents , 2001, Expert opinion on investigational drugs.

[29]  T. Morrison Structure and function of a paramyxovirus fusion protein. , 2003, Biochimica et biophysica acta.

[30]  Christoph Grundner,et al.  Tyrosine Sulfation of Human Antibodies Contributes to Recognition of the CCR5 Binding Region of HIV-1 gp120 , 2003, Cell.

[31]  T. Krusat,et al.  Heparin-dependent attachment ofrespiratory syncytial virus (RSV) to host cells , 1997, Archives of Virology.

[32]  E. De Clercq,et al.  In vitro and in vivo inhibition of ortho- and paramyxovirus infections by a new class of sulfonic acid polymers interacting with virus-cell binding and/or fusion , 1994, Antimicrobial Agents and Chemotherapy.

[33]  Keiji Fukuda,et al.  Mortality associated with influenza and respiratory syncytial virus in the United States. , 2003, JAMA.

[34]  T. Cihlar,et al.  Inhibition of Respiratory Syncytial Virus Fusion by the Small Molecule VP-14637 via Specific Interactions with F Protein , 2003, Journal of Virology.

[35]  Christine Katlama,et al.  Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. , 2003, The New England journal of medicine.

[36]  M. Lawrence,et al.  The structural biology of type I viral membrane fusion , 2003, Nature Reviews Molecular Cell Biology.