Examination of a fusogenic hexameric core from human metapneumovirus and identification of a potent synthetic peptide inhibitor from the heptad repeat 1 region.
Paramyxoviruses are a leading cause of childhood illness worldwide. A recently discovered paramyxovirus, human metapneumovirus (hMPV), has been studied by our group in order to determine the structural relevance of its fusion (F) protein to other well-characterized viruses utilizing type I integral membrane proteins as fusion aids. Sequence analysis and homology models suggested the presence of requisite heptad repeat (HR) regions. Synthetic peptides from HR regions 1 and 2 (HR-1 and -2, respectively) were induced to form a thermostable (melting temperature, approximately 90 degrees C) helical structure consistent in mass with a hexameric coiled coil. Inhibitory studies of hMPV HR-1 and -2 indicated that the synthetic HR-1 peptide was a significant fusion inhibitor with a 50% inhibitory concentration and a 50% effective concentration of approximately 50 nM. Many viral fusion proteins are type I integral membrane proteins utilizing the formation of a hexameric coiled coil of HR peptides as a major driving force for fusion. Our studies provide evidence that hMPV also uses a coiled-coil structure as a major player in the fusion process. Additionally, viral HR-1 peptide sequences may need further investigation as potent fusion inhibitors.
Miller
Scott A
SA
Vanderbilt University, Department of Chemistry, Station B 351822, Nashville, TN 37235-1822, USA.
Tollefson
Sharon
S
Crowe
James E
JE
Williams
John V
JV
Wright
David W
DW
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D029121:Metapneumovirus / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D014758:Viral Core Proteins / Q000737:chemistry / Q000502:physiology; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000502:physiology
D000998:Antiviral Agents; D010455:Peptides; D014758:Viral Core Proteins; D014760:Viral Fusion Proteins