A new intracellular targeting motif in the cytoplasmic tail of the spike protein may act as a target to inhibit SARS-CoV-2 assembly.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a threat to global public health, underscoring the urgent need for the development of preventive and therapeutic measures. The spike (S) protein of SARS-CoV-2, which mediates receptor binding and subsequent membrane fusion to promote viral entry, is a major target for current drug development and vaccine design. The S protein comprises a large N-terminal extracellular domain, a transmembrane domain, and a short cytoplasmic tail (CT) at the C-terminus. CT truncation of the S protein has been previously reported to promote the infectivity of SARS-CoV and SARS-CoV-2 pseudoviruses. However, the underlying molecular mechanism has not been precisely elucidated. In addition, the CT of various viral membrane glycoproteins play an essential role in the assembly of virions, yet the role of the S protein CT in SARS-CoV-2 infection remains unclear. In this study, through constructing a series of mutations of the CT of the S protein and analyzing their impact on the packaging of the SARS-CoV-2 pseudovirus and live SARS-CoV-2 virus, we identified V1264L1265 as a new intracellular targeting motif in the CT of the S protein, that regulates the transport and subcellular localization of the spike protein through the interactions with cytoskeleton and vesicular transport-related proteins, ARPC3, SCAMP3, and TUBB8, thereby modulating SARS-CoV-2 pseudovirus and live SARS-CoV-2 virion assembly. Either disrupting the V1264L1265 motif or reducing the expression of ARPC3, SCAMP3, and TUBB8 significantly repressed the assembly of the live SARS-CoV-2 virion, raising the possibility that the V1264L1265 motif and the host responsive pathways involved could be new drug targets for the treatment of SARS-CoV-2 infection. Our results extend the understanding of the role played by the S protein CT in the assembly of pseudoviruses and live SARS-CoV-2 virions, which will facilitate the application of pseudoviruses to the study of SARS-CoV-2 and provide potential strategies for the treatment of SARS-CoV-2 infection.

SARS-CoV-2 Omicron Variant is Expected to Retain Most of the Spike Protein Specific Dominant T-Cell Epitopes Presented by COVID-19 Vaccines - Worldwide, 2021.

What is already known about this topic?: The newly emerged variant of Omicron, which carries many of the mutations found in other variants of concern (VOCs), as well as a great number of new mutations that may enhance its immune escape, has spread rapidly around the world. This has raised public concern about the effectiveness of the current coronavirus disease 2019 (COVID-19) vaccine. What is added by this report?: In this study, different bioinformatic softwares were applied to predict the dominant Omicron spike (S) protein cytotoxic T lymphocyte (CTL) and T helper (Th) epitopes in representative world population and Chinese population. Compared to the original severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein, limited mutations were identified within the dominant CTL and Th epitopes in Omicron variant. What are the implications for public health practice?: The results of this study suggested that the current COVID-19 vaccine-induced T-cell immunity may still provide significant protection against Omicron variant infection in fully vaccinated individuals.