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Abstract
The COVID-19 pandemic that began in late 2019 continues with new challenges arising due to antigenic drift as well as individuals who cannot or choose not to take the vaccine. There is therefore an urgent need for additional therapies that complement vaccines and approved therapies such as antibodies in the fight to end or slow down the pandemic. SARS-CoV-2 initiates invasion of the human target cell through direct contact between the receptor-binding domain of its Spike protein and its cellular receptor, angiotensin-converting enzyme-2 (ACE2). The ACE2 and S1 RBD interaction, therefore, represents an attractive therapeutic intervention to prevent viral entry and spread. In this study, we developed a proximity-based AlphaScreen™ assay that can be utilized to quickly and efficiently screen for inhibitors that perturb the ACE2 : S1 RBD interaction. We then designed several peptides candidates from motifs in ACE2 and S1 RBD that play critical roles in the interaction, with and without modifications to the native sequences. We also assessed the possibility of reprofiling of candidate small molecules that previously have been shown to interfere with the viral entry of SARS-CoV. Using our optimized AlphaScreen™ assay, we evaluated the activity and specificity of these peptides and small molecules in inhibiting the binding of ACE2 : S1 RBD. This screen identified cepharanthine as a promising candidate for development as a SARS-CoV-2 entry inhibitor.
Highlights
Since its emergence, COVID-19, the disease caused by the novel SARS-CoV-2, has killed close to 3 million people worldwide and costs world economies trillions of dollars [1, 2]
New variants such as B.1.351 and P.1 contain mutations in their Spike protein that increase virulence and reinfection rates and confer resistance to antibodies induced by all available vaccines [7,8,9,10,11,12,13]. e ongoing SARS-CoV-2 antigenic drift and the fact that many people are not becoming vaccinated due to issues related to vaccine hesitancy, access, or health issues such as an immunocompromised immune system [14,15,16] suggest that additional COVID-19 therapeutics are needed to fight this pandemic
Our analysis showed that amino acids of S1 RBD that recognize ACE2 during attachment come from loops 2, 4 and β-sheet 6 and they are highlighted by residues such as 484(E), 486(F), 487(N), 493(Q), 498(Q), 501(N), and 505(Y). erefore, we designed a 23-mer fragment that stretches from 483 to 505. is peptide fragment (Pep 6) was predicted to contribute to about 62% of total interface binding (Figure 3(a))
Summary
COVID-19, the disease caused by the novel SARS-CoV-2, has killed close to 3 million people worldwide and costs world economies trillions of dollars [1, 2]. Many estimates show that over 70% vaccine coverage and uptake is needed in most countries to reach herd immunity, with the US needing to vaccinate about 80–85% of its population [3,4,5,6]. In this context, the challenges posed by the emergence of new SARS-CoV-2 variants threaten to derail plans for a vaccinedriven end to the pandemic. New variants such as B.1.351 and P.1 contain mutations in their Spike protein that increase virulence and reinfection rates and confer resistance to antibodies induced by all available vaccines [7,8,9,10,11,12,13]. e ongoing SARS-CoV-2 antigenic drift and the fact that many people are not becoming vaccinated due to issues related to vaccine hesitancy, access, or health issues such as an immunocompromised immune system [14,15,16] suggest that additional COVID-19 therapeutics are needed to fight this pandemic
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