Severe acute respiratory syndrome coronavirus entry into host cells: Opportunities for therapeutic intervention.
A novel human coronavirus (CoV) has been identified as the etiological agent that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. The spike (S) protein of this virus is a type I surface glycoprotein that mediates binding of the virus to the host receptor and the subsequent fusion between the viral and host membranes. Because of its critical role in viral entry, the S protein is an important target for the development of anti-SARS CoV therapeutics and prophylactics. This article reviews the structure and function of the SARS CoV S protein in the context of its role in virus entry. Topics that are discussed include: the interaction between the S1 domain of the SARS spike protein and the cellular receptor, angiotensin converting enzyme 2 (ACE2), and the structural features of the ectodomain of ACE2; the antigenic determinants presented by the S protein and the nature of neutralizing monoclonal antibodies that are elicited in vivo; the structure of the 4,3-hydrophobic heptad repeats HR1 and HR2 of the S2 domain and their interaction to form a six-helical bundle during the final stages of fusion. Opportunities for the design and development of anti-SARS agents based on the inhibition of receptor binding, the therapeutic uses of S-directed monoclonal antibodies and inhibitors of HR1-HR2 complex formation are presented.
Yeung
Kap-Sun
KS
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O. Box 5100, Wallingford, Connecticut 06492, USA. KapSun.Yeung@bms.com
Yamanaka
Gregory A
GA
Meanwell
Nicholas A
NA
D000085962:Angiotensin-Converting Enzyme 2; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000998:Antiviral Agents / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008562:Membrane Glycoproteins / Q000378:metabolism; D008956:Models, Chemical; D008957:Models, Genetic; D008958:Models, Molecular; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000472:pathogenicity* / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; C578553:spike protein, mouse hepatitis virus; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2