Abstract

The emergence and wide spreading of novel coronavirus SARS-CoV-2 represent a serious threat to global human health, which are highly demanding new strategies for prevention and therapy. SARS-CoV-2 has a linear single-stranded positive-sense RNA genome, encoding 4 structural proteins [spike (S), envelope (E), membrane (M), and nucleocapsid (N)]. Among these proteins, the S protein is the major focus of current research, as it facilities viral attachment, entry and membrane fusion.1 The infection of host cells is initiated by the interaction of the viral S protein with receptors on the cell surface, hence it has a crucial role in the spread of the virus. There is surely an urgent need to develop a vaccine to halt the viral infection and curb the pandemic.

The S protein is the principal target of the humoral immune response. It is a trimetric class I fusion protein consisting of two subunits: S1 subunit has a receptor binding domain (RBD) that interacts with its host cell reception, and the S2 subunit mediates membrane fusion for viral replication.2 The human angiotensin-converting enzyme 2 (hACE2) is the entry receptor for SARS-CoV-2.3 As vaccine developments aim to elicit adaptive immunity via an antibody response at the sites of viral entry, one main strategy for vaccine development is to use peptides derived from S protein as the antigen to generate the antibody. The S-peptide induced antibody can potentially block the entry of SARS-CoV-2 to the host cell.

To solve the heterogeneity problem of glycopeptides/proteins obtained from biological systems, we aim to develop a chemical synthesis strategy to generate structure-defined glycosylated peptides derived from the spike protein, with which to develop vaccine candidates for SARS-CoV-2. By adopting the synthetic approach, we are also able to modify the protein with precision and flexibility, including homogenously glycosylated epitopes that are difficult to obtain through expression or isolation. Extensive investigation of the structure-activity relationship of the S RBD glycopeptides shall be followed, for eliciting candidates with the best immunogenicity and efficacy.

Reference:

1. Li, F. Annu Rev Virol, 2016, 3 (1), 237-261.
2. Watanabe, Y.; Allen, J. D.; Wrapp, D.; McLellan, J. S.; Crispin, M. Science, 2020, 369 (6501), 330-333.
3. Zhang, H.; Penninger, J. M.; Li, Y.; Zhong, N.; Slutsky, A. S. Intensive Care Med, 2020, 46 (4), 586-590.

4. Zhang, Y.; Xu, C.; Lam, H. Y.; Lee, C. L.; Li, X. Proc Natl Acad Sci U S A, 2013, 110 (17), 6657-62.