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The pH Effects on SARS-CoV and SARS-CoV-2 Spike Proteins in the Process of Binding to hACE2.

ABSTRACT: COVID-19 has been threatening human health since the late 2019, which has significant impact on human health and economy. Understanding the SARS-CoV-2 and other coronaviruses is important to develop effective treatments for COVID-19 and other coronaviruses-caused diseases. In this work, we applied multi-scale computational approaches to study the electrostatic features of spike (S) proteins for SARS-CoV and SARS-CoV-2. From our results, we found thatSARS-CoV and SARS-CoV-2 have similar charge distributions and electrostatic features when binding with the human angiotensin-converting enzyme 2 (hACE2). The energy pH-dependence calculation srevealed that the complex structures of hACE2 and the S proteins of SARS-CoV/SARS-CoV-2 are stable at pH values ranging from 7.5 to 9. Molecular dynamics simulations were performed using NAMD to investigate the hydrogen bonds between S proteins and hACE2. From the MD simulations it was found that SARS-CoV-2 has four pairsof essential hydrogenbonds (high occupancy, >80%), while SARS-CoV has three pairs, which indicates the SARS-CoV-2 S protein has relatively more robust binding strategy than SARS-CoVS protein.Four key residues forming essential hydrogen bonds from SARS-CoV-2 are identified, which are potential drug targets for COVID-19 treatments. The findings in this study shed lights on the current and future treatments for COVID-19 and other coronaviruses-caused diseases.

SUBMITTER: Xie Y

PROVIDER: S-EPMC8437318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Nobody knows when the COVID-19 pandemic will end or when and where the next coronavirus will outbreak. Therefore, it is still necessary to develop SARS-CoV-2 inhibitors for different variants or even the new coronavirus. Since SARS-CoV-2 uses its surface spike-protein to recognize hACE2, mediating its entry into cells, ligands that can specifically recognize the spike-protein have the potential to prevent infection. Methods: We have recently discovered DNA aptamers against the S2-domain of the WT spike-protein by exploiting the selection process called SELEX. After optimization, among all candidates, the aptamer S2A2C1 has the shortest sequence and the best binding affinity toward the S2-protein. More importantly, the S2A2C1 aptamer does not bind to the RBD of the spike-protein, but it efficiently blocks the spike-protein/hACE2 interaction, suggesting an RBD-independent inhibition approach. To further improve its performance, we conjugated the S2A2C1 aptamer with a reported anti-RBD aptamer, S1B6C3, using various linkers and constructed hetero-bivalent fusion aptamers. Binding affinities of mono and fusion aptamers against the spike-proteins were measured. The inhibition efficacies of mono and fusion aptamers to prevent the hACE2/spike-protein interaction were determined using ELISA. Results: Anti-spike-protein aptamers, including S2A2C1 and S1B6C3-A5-S2A2C1, maintained high binding affinity toward the WT, Delta, and Omicron spike-proteins and high inhibition efficacies to prevent them from binding to hACE2, rendering them well-suited as diagnostic and therapeutic molecular tools to target SARS-CoV-2 and its variants. Conclusions: Overall, we discovered the anti-S2 aptamer, S2A2C1, which inhibits the hACE2/spike-protein interaction via an RBD-independent approach. The anti-S2 and anti-RBD aptamers were conjugated to obtain the fusion aptamer, S1B6C3-A5-S2A2C1, which recognizes the spike-protein by an RBD-dependent approach. Our strategies, which discovered aptamer inhibitors targeting the highly conserved S2-protein, as well as the design of fusion aptamers, can be used to target new coronaviruses as they emerge.

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The pH Effects on SARS-CoV and SARS-CoV-2 Spike Proteins in the Process of Binding to hACE2.

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