Anti-coronaviral activities of natural products and their derivatives
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Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has had a profound impact on global
health and economies, highlighting the urgent need for novel, effective antiviral agents.
Following its first report in Wuhan, China in 2019, it quickly spread around the world with
more than 7 million fatalities and over 777 million reported cases as of February 2025. While
vaccines have played a crucial role in decreasing disease severity, the continuous emergence
of new mutant strains, particularly the Omicron subvariants, poses a significant challenge.
These variants have demonstrated an increased ability to evade immune detection, reducing the
efficacy of existing vaccines and antibody therapies. Moreover, the period between disease
outbreaks has become shorter, and there is a possibility that more viral epidemics will occur
soon. Thus, the identification of pan-coronaviral inhibitors, capable of targeting viral structures
essential for replication and host entry, is crucial for pandemic preparedness and long-term
antiviral strategies. The present PhD thesis demonstrates that natural product derivatives can
serve as pan-coronaviral inhibitors.
The main protease (Mpro or 3CLpro) in coronaviruses represents a promising specific drug target
as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that
does not exist in human host proteases. Here we explored potential natural pan-coronavirus
drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment
targets. Hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited Mpro of SARS-CoV-2,
while hypericin and isorhamnetin inhibited Mpro of SARS-CoV-1; hypericin showed inhibitory
effects toward Mpro of MERS-CoV. Microscale thermophoresis confirmed the binding of these
compounds to Mpro with high affinity. Cytotoxity results showed that rosmarinic acid and
luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin showed
slightl toxicity. These findings highlight hypericin’s potential as a lead compound for further
development in antiviral drug discovery as a pan-anti-coronaviral agent by binding to and
inhibiting Mpro of several human-pathogenic coronaviruses.
The receptor-binding domain (RBD) within the S1 subunit plays a pivotal role in binding to
the angiotensin-converting enzyme 2 (ACE2) receptor on host cells, facilitating viral entry,
represents a promising target for therapeutic intervention. We demonstrated that a
diketopiperazine/piperidine alkaloid and natural isoquinoline derivatives inhibited SARS-CoV-
2 pseudovirus and live virus entry in host cells while showing low toxicity. Microscale
thermophoresis revealed these compounds strongly bound to the RBDs of SARS-CoV-2,III
SARS-CoV-2 XBB, SARS-CoV-1, MERS-CoV, and HCoV-HKU1, with their Kd values
increasing as RBD sequence similarity decreased. These findings showed that these
compounds, should be considered for further development as potential pan-coronavirus entry
inhibitors.