Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease

Abstract

Analogues and derivatives of natural nucleosides/nucleotides are considered among the most successful bioactive species of drug-like compounds in modern medicinal chemistry, as they are well recognized for their diverse and efficient pharmacological activities in humans, especially as antivirals and antitumors. Coronavirus disease 2019 (COVID-19) is still almost incurable, with its infectious viral microbe, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continuing to wreak devastation around the world. This global crisis pushed all involved scientists, including drug discoverers and clinical researchers, to try to find an effective and broad-spectrum anti-COVID-19 drug. Didanosine (2′,3′-dideoxyinosine, DDI) is a synthetic inosine/adenosine/guanosine analogue and highly active antiretroviral therapeutic agent used for the treatment of human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS). This potent reverse-transcriptase inhibitor is characterized by proven strong pharmacological effects against the viral genome, which may successfully take part in the effective treatment of SARS-CoV-2/COVID-19. Additionally, targeting the pivotal SARS-CoV-2 replication enzyme, RNA-dependent RNA polymerase (RdRp), is a very successful tactic to combat COVID-19 irrespective of the SARS-CoV-2 variant type because RdRps are broadly conserved among all SARS-CoV-2 strains. Herein, the current study proved for the first time, using the in vitro antiviral evaluation, that DDI is capable of potently inhibiting the replication of the novel virulent progenies of SARS-CoV-2 with quite tiny in vitro anti-SARS-CoV-2 and anti-RdRp EC 50 values of around 3.1 and 0.19 μM, respectively, surpassing remdesivir together with its active metabolite (GS-441524). Thereafter, the in silico computational interpretation of the biological results supported that DDI strongly targets the key pocket of the SARS-CoV-2 RdRp main catalytic active site. The ideal pharmacophoric characteristics of the ligand DDI make it a typical inhibiting agent of SARS-CoV-2 multiplication processes (including high-fidelity proofreading), with its elastic structure open for many kinds of derivatization. In brief, the present results further uphold and propose the repurposing potentials of DDI against the different types of COVID-19 and convincingly motivate us to quickly launch its extensive preclinical/clinical pharmacological evaluations, hoping to combine it in the COVID-19 therapeutic protocols soon.

Dual computational and biological assessment of some promising nucleoside analogs against the COVID-19-Omicron variant

“…This established in vitro anti-COVID-19 multiassay (including the cytotoxicity test), which was precisely designed for the valuation and rating of the pure anti-SARS-CoV-2 activities of potential anti-COVID-19 agents, is based mainly upon the authentic procedures of Rabie ( Rabie, 2021b , Rabie, 2021c , Rabie, 2021d , Rabie, 2021e , Rabie, 2022a , Rabie, 2022b ). The complete procedures were carried out in a specialized biosafety level 3 (BSL-3) laboratory.…”

“…Compounds and drugs that act to satisfy mainly the first need of the three ones are relatively few to date. Of them, only nucleoside analogs/derivatives (NAs/NDs) and polyphenolics (PPhs) have shown significant successful progress as coronaviral-2 inhibitors ( Mahase, 2021 , Imran et al, 2021 , Moirangthem and Surbala, 2021 , Yan and Muller, 2020 , Brunotte et al, 2021 , Rabie, 2022a , Rabie, 2022b , Cai et al, 2020 , Rabie, 2021c , Rabie, 2021d , Rabie, 2021e , Raj et al, 2022 , Raj et al, 2021 ). NAs are naturally more promising and highly biotolerated as antiviral therapeutics ( Chien et al, 2020 ).…”

“…NAs are naturally more promising and highly biotolerated as antiviral therapeutics ( Chien et al, 2020 ). Some new and repositioned efficacious nucleoside-like compounds are nowadays (and/or since 2020) under vast pharmacological and clinical investigations to be esteemed as effective potential anti-SARS-CoV-2/anti-COVID-19 medicines, e.g., nirmatrelvir ( Mahase, 2021 ), molnupiravir ( Imran et al, 2021 ), remdesivir ( Moirangthem and Surbala, 2021 ), GS-441524 ( Yan and Muller, 2020 , Brunotte et al, 2021 ), GS-443902 ( Moirangthem and Surbala, 2021 , Yan and Muller, 2020 , Brunotte et al, 2021 ), cordycepin ( Rabie, 2022a ), didanosine ( Rabie, 2022b ), and favipiravir ( Cai et al, 2020 ).…”

“…Tactical nucleoside analogism is among the favorable therapeutic choices in drug designers' and pharmaceutical chemists' brains to fight and stop the coronavirus multiplication inside the human body ( Imran et al, 2021 , Moirangthem and Surbala, 2021 , Yan and Muller, 2020 , Brunotte et al, 2021 , Rabie, 2022a , Rabie, 2022b , Cai et al, 2020 , Chien et al, 2020 ). In this dual COVID-19 therapeutic tactic, the used nucleoside/nucleotide analog makes use of its high similarity with the normal inbred nucleosides and nucleotides to effectively misguide and deceive the SARS-CoV-2 RdRp (the nonstructural protein complex 12/7/8 or nsp12-nsp7-nsp8) and ExoN (the nonstructural protein complex 14/10 or nsp14-nsp10) enzymes ( Chien et al, 2020 ).…”

“…Nsp12-nsp7-nsp8 and nsp14-nsp10 protein complexes are very indispensable enzymes in the replication/proofreading of the coronaviral-2 genome, and thus, their strong inhibition will significantly block the replication of SARS-CoV-2 particles. Nucleoside-like agents discompose both RdRp and ExoN enzymes through complete incorporation in the viral RNA genetic strands in place of the correct naturally-occurring nucleosides/nucleotides, resulting in repeated excessive ambiguous coding and premature termination of RNA synthesis with the formation of vague RNA strands at the end; these faulty strands represent abnormal noninfectious and inactive particles, hence there would not be any further multiplication of the virus ( Rabie, 2022a , Rabie, 2022b , Chien et al, 2020 ). Some of the aforementioned anti-COVID-19 agents, e.g., molnupiravir and remdesivir ( Fig.…”