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By Biosan | 22 March 2022

ACS Omega: Cordycepin leads in antiviral activity and may promote comprehensive treatment of COVID-19

Recently, ACS Omega, a journal of the American Chemical Society, published an article by Dr Amgad M Rabie and his team from the Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura Drug Discovery Research Laboratory, Egypt, entitled Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV2 Replication.

The journal claims that Cordycepin( 3’-deoxyadenosine) is at the leading edge of antiviral activity and can effectively contribute to the comprehensive treatment of Covid-19.

Figure 1 Chemical structure of remdesivir, GS-441524, cyanorona-20, and favipiravir.
Studies have shown that cordycepin could easily involve in inhibiting the replication and survival of the new coronavirus COVID-19 itself, with potent broad-spectrum antiviral activities (including activity against the latest SARS-CoV2 strain). This anti-SARS-CoV-2 effect of Cordycepin is mainly due to its structural similarity to human adenosine.
 Dr Amgad suggests that cordycepin could effectively inhibit the coronaviral replication (i.e., act as a SARS-CoV-2 replication inhibitor) by significantly reducing the number of replicated coronaviral copies, which is expected to result from locking mainly the genomic RNA synthesis occurred via the SARS-CoV-2 RdRp, using the nucleoside analogism strategy (as previously mentioned). In this effective mechanism of anti-RNA action, the nucleoside-like cordycepin molecule is first readily phosphorylated to its mono-, di-, and triphosphate forms (i.e., its nucleotide analogues) intracellularly, then the superactive nucleotide analogue cordycepin triphosphate (Cor-TP) can be easily incorporated into RNA in place of the endogenous chemicosimilar bionucleotide adenosine triphosphate (ATP); this inhibits and terminates transcription elongation and synthesis of viral RNA strands in all stages (i.e., acts as an RNA elongation inhibitor due to the hydroxyl moiety absence at the 3′ position of the molecule, this one-hydroxyl group deficiency significantly antagonizes the SARS-CoV-2 RdRp activity as previously mentioned), giving incomplete disrupted premature RNAs in the developing mRNA strands and viral genomes, and finally, this ambiguous coding leads to strong inhibition of SARS-CoV-2 copying/replication and generation of inactive, noninfectious, mutated, useless, nonpathogenic, and nonviral/non-SARS-CoV-2 particles instead of the active, parent, correct, original, infectious, pathogenic, and virulent SARS-CoV-2 particles (Figure 2). ( ACS Omega, 2022)

Figure 2. Illustration of the newly proposed mechanism of anti-SARS-CoV-2 action of cordycepin. ( ACS Omega,2022)
In addition, cordycepin can alleviate and link the severe symptoms and sequelae characteristic of the new coronavirus, mainly related to the severe symptoms and sequelae of SARS-CoV-2 attack on the respiratory and cardiovascular systems of patients.
The data obtained from using the ProTox-II (Prediction of Toxicity of Chemicals) Virtual Laboratory disclosed the predicted relative biosafety of the compound cordycepin (over many investigational potential anti-COVID-19 drugs) and proves that cordycepin has a high safety profile in terms of galvanization of different organs and adverse outcomes.
At the same time, the article also showed a much higher antiviral effect of cordycepin against the emerging SARS-CoV-2 variant compared to the two positive control reference drugs, remdesivir and GS-441524 (the placebo drug dimethyl sulfoxide DMSO), which were 10.5 and 7.8 times more effective year-on-year.

Table 1. Anti-SARS-CoV-2/Anti-COVID-19 Activities (along with Cytotoxicities) of the Target Drug Cordycepin (Using Both Remdesivir and GS-441524 as the Positive Control/Reference Drugs, and DMSO as the Negative Control/Placebo Drug) against SARS-CoV-2 (VOC-202012/01 strain) in Vero E6 Cells

Cordycepin is an ideal druglike compound since it fully obeys Lipinski’s rule of five (Ro5) with no violations. Cordycepin is also a highly biocompatible molecule with enhanced abilities to pass through biologic membranes when compared with the adenosine molecule due to the relatively higher lipophilic characters resulting from the shortage of a hydroxyl group (i.e., the cordycepin molecule is less hydrophilic than the adenosine molecule).Metabolic similarity with the biosimilar adenosine molecule greatly helps cordycepin in tricking the human biological system and doing its intended therapeutic roles. ” ( ACS Omega,2022)
In the conclusion of the article, Dr. Amgad M Rabie and his team also call on the scientific community to increase preclinical and clinical studies on cordycepin against COVID-19, to carefully evaluate the efficacy and safety of cordycepin as monotherapy, or to choose dual combination therapy with DPM or triple combination therapy (with DPM and PTN) for all types of combination therapy and prevention and treatment of COVID-19.
Cordycepin is a known unique natural adenosine analogue, mainly derived from Chrysanthemum and Cordyceps. It is one of the most important and promising natural phytotherapeutics in the world, as it has been shown to be effective in antiviral, antifungal, antitubercular, antimalarial, antioxidant, antitumor, antimetastatic, antihyperglycemic, and antihypertensive effects.

Reference: Potent Inhibitory Activities of the Adenosine Analogue Cordycepin on SARS-CoV-2 Replication
                   Amgad M. Rabie
                   ACS Omega 2022 7 (3), 2960-2969
                   DOI: 10.1021/acsomega.1c05998