Severe acute respiratory syndrome (SARS) is a newly emerging infectious disease caused by a novel coronavirus, SARS-coronavirus (SARS-CoV). The SARS-CoV spike (S) protein is composed of two subunits; the S1 subunit contains a receptor-binding domain that engages with the host cell receptor angiotensin-converting enzyme 2 and the S2 subunit mediates fusion between the viral and host cell membranes. The S protein plays key parts in the induction of neutralizing-antibody and T-cell responses, as well as protective immunity, during infection with SARS-CoV. In this Review, we highlight recent advances in the development of vaccines and therapeutics based on the S protein. SARS-CoV is an enveloped, single and positive-stranded RNA virus2. Its genome RNA encodes a non-structural replicase polyprotein and structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins3-5. SARS-CoV, a zoonotic virus, resides in hosts that form its natural reservoir, such as bats, but can also infect intermediate hosts, such as small animals (for example, palm civets), before being transmitted to humans6-8. SARS-CoV can infect and replicate in several cell types in the human body and causes serious pathological changes Zoonotic virusA virus that normally exists in vertebrate animals, but can also be transmitted to humans and can cause disease in both animals and humans. Box 1 Pathology of SARS and the life cycle of SARS-CoV infectionSevere acute respiratory syndrome-coronavirus (SARS-CoV) spreads primarily through droplets (respiratory secretions) and close person-to-person contact. After the virus enters into the body, it binds to primary target cells that express abundant virus receptor, the angiotensin-converting enzyme 2 (ACE2), including pneumocytes and enterocytes in the respiratory system. The virus enters and replicates in these cells. The matured virions are then released to infect new target cells121 (FIG. 1). SARS-CoV can also infect mucosal cells of intestines, tubular epithelial cells of kidneys, epithelial cells of renal tubules, cerebral neurons and immune cells122,123. Infectious viral particles in patients with SARS can be excreted through respiratory secretions, stool, urine and sweat. SARS-CoV infection damages lung tissues owing to elevated levels of production and activation of proinflammatory chemokines and cytokines124, resulting in atypical pneumonia with rapid respiratory deterioration and failure.Neutralizing antibodies and/or T-cell immune responses can be raised directly against several SARS-CoV proteins21-23, but mainly target the S protein20,24-26, suggesting that S protein- Structure of the SARS-CoV S proteinThe spikes of SARS-CoV are composed of trimers of S protein, which belongs to a group of class I viral fusion glycoproteins that also includes HIV glyco-protein 160 (Env), influenza haemagglutinin (HA), paramyxovirus F and Ebola virus glycoprotein28. The SARS-CoV S protein encodes a surface glycoprotein precursor that is predicted to be 1,255 amino acids in l...
The outbreak of Coronavirus Disease 2019 has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could crossreact with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
The recent outbreak of coronavirus disease caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be defined. Therefore, we herein established a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted the HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241-and 149-fold more potent than the original EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, and potently inhibited the replication of 5 live human coronaviruses examined, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs.
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