Identification and characterization of malaria box compounds possessing inhibition effect on the SARS-CoV-2 spike protein

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since 2019. Although current treatments are available for patients with mild-to-moderate symptoms, they have limited efficacy in severe COVID-19 and can cause side effects in some patient groups, particularly in older or nonhealthy individuals. Developing new drugs that can better manage severe disease, reduce mortality rates, and broaden the treatment options are necessary.

Objective:To evaluate the binding interactions and inhibitory effect of malaria box compounds on the B-cell epitope regions of SARS-CoV-2 spike protein.

Methods: Molecular docking of 400 malaria box compounds against the predicted B-cell epitopes of the spike protein was performed. The inhibitory effects of malaria box compounds on the spike RBD were determined using competitive enzyme-linked immunoassay. The binding affinity between malaria box compounds and non-RBD epitopes was examined by surface plasmon resonance (SPR) assays.

Results: MMV000563 and MMV019690 were the top-scoring compounds that could bind to the spike RBD, with inhibitory effects at 45.6% and 47.0%, respectively. However, competitive ELISA revealed that the binding of the spike RBD to human angiotensin-converting enzyme 2 was most strongly inhibited by MMV665881 (P = 0.004). Based on SPR results, MMV019881, MMV020912, and MMV000753 showed the highest binding affinities to their respective epitope peptides in the non-RBD regions of the spike protein.

Conclusion: These results demonstrate the ability of malaria box compounds to bind to and interfere with SARS-CoV-2 spike protein, which may be beneficial for COVID-19 treatment.