Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir “S-217622”: A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species

Abstract

Lately, nitrogenous heterocyclic antivirals, such as nucleoside-like compounds, oxadiazoles, thiadiazoles, triazoles, quinolines, and isoquinolines, topped the therapeutic scene as promising agents of choice for the treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their accompanying ailment, the coronavirus disease 2019 (COVID-19). At the same time, the continuous emergence of new strains of SARS-CoV-2, like the Omicron variant and its multiple sublineages, resulted in a new defiance in the enduring COVID-19 battle. Ensitrelvir (S-217622) is a newly discovered orally active noncovalent nonpeptidic agent with potential strong broad-spectrum anticoronaviral activities, exhibiting promising nanomolar potencies against the different SARS-CoV-2 variants. S-217622 effectively and nonspecifically hits the main protease (M pro ) enzyme of a broad scope of coronaviruses. Herein, in the present computational/biological study, we tried to extend these previous findings to prove the universal activities of this investigational agent against any coronavirus, irrespective of its type, through synchronously acting on most of its main unchanged replication enzymes/proteins, including (in addition to the M pro ), e.g., the highly conserved RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN). Biochemical evaluation proved, using the in vitro anti-RdRp/ExoN bioassay, that S-217622 can potently inhibit the replication of coronaviruses, including the new virulent strains of SARS-CoV-2, with extremely minute in vitro anti-RdRp and anti-RdRp/ExoN half-maximal effective concentration (EC 50 ) values of 0.17 and 0.27 μM, respectively, transcending the anti-COVID-19 drug molnupiravir. The preliminary in silico results greatly supported these biochemical results, proposing that the S-217622 molecule strongly and stabilizingly strikes the key catalytic pockets of the SARS-CoV-2 RdRp's and ExoN's principal active sites predictably via the nucleoside analogism mode of anti-RNA action (since the S-217622 molecule can be considered as a uridine analog). Moreover, the idealistic druglikeness and pharmacokinetic continued...

Promising Experimental Anti-SARS-CoV-2 Agent “SLL-0197800”: The Prospective Universal Inhibitory Properties against the Coming Versions of the Coronavirus

“…Interestingly, a recent paper (published by our research team in the ACS Omega journal in 2023) investigated and explored the inhibitory potential of the novel anti-SARS-CoV-2 ensitrelvir against the same enzymatic replication system “RdRp-ExoN” . This drug acts on the SARS-CoV-2 particles primarily through noncovalently blocking the catalytic actions of the viral M pro enzyme .…”

“…The paper of ensitrelvir principally highlighted the possible tactical mechanism of action of the drug in competitively inhibiting both the enzymes RdRp and ExoN via the nucleoside analogism strategy. Although it was proved in the present paper that the SLL-0197800 molecule might similarly act as an anti-SARS-CoV-2 agent also through this additional dual-action mode (anti-RdRp-ExoN activities), but the compound SLL-0197800 might possibly have many striking merits above the compound ensitrelvir comprehensively. , First, with a much smaller molecular weight of 377.83 Da, the SLL-0197800 molecule owns distinctly better pharmacokinetic/pharmacodynamic capabilities and characteristics than those of the ensitrelvir molecule (which has a molecular weight of 531.88 Da) in the in vivo and clinical environments (some of these properties are previously illustrated in Figure B). Second, from the drug-likeness point of view, the ensitrelvir molecule violates Lipinski’s Rule of 5 (Ro5) with two violations at least (in addition to its large over-500 molecular weight, the molecule possesses 11 H-bond acceptors, i.e., more than 10 oxy(nitro)gen atoms), unlike the SLL-0197800 molecule that fully obeys and fulfills these drug-likeness requirements without any violation at all.…”

“…Seventh, from the pharmacological/toxicological point of view, the dominant non-nucleosidic nature of the chemical structure of the anticoronaviral agent SLL-0197800 helps to prevent incidence of many of the problematically irritating bioactions and critical adverse effects that, on the other hand, might occur with the nucleoside analogue ensitrelvir due to interruption of and/or interference with several biological pathways in humans. Eighth, from the synthetic organic chemical point of view, the compound SLL-0197800 could be synthesized via cheaper and simpler designed methods than those for the compound ensitrelvir, affording an inexpensive pharmaceutical product at the end. , Ninth, from the primary therapeutic point of view, SLL-0197800 has more potent net in vitro anti-SARS-CoV-2 activities (EC 50 values of lower than 0.11 μM, reaching as low as 0.077 μM) than those of ensitrelvir (EC 50 values of higher than 0.29 μM, reaching as high as 0.50 μM). , Tenth, the current discovery for SLL-0197800 directly opens the door for the establishment of the first isoquinoline class of compounds, i.e., the first non-nucleosidic class of drugs or the premier non-nucleoside inhibitors (NNIs), with a triple mode of anticoronaviral action (anti-SARS-CoV-2-M pro -RdRp-ExoN activities), unlike ensitrelvir which is almost a classical antiviral nucleoside-like compound.…”

“…Third, the equiponderant octanol/water partition coefficient of SLL-0197800 (Log P = 3.82) is higher than that of ensitrelvir (Log P = 2.28), giving the SLL-0197800 molecule stronger lipophilic properties that significantly aid in higher bioavailability from the oral route together with more rapid/efficient penetration of the living tissues (especially the primary sites of action, e.g., stomach, intestine, lungs, and blood vessels) for this drug (as compared to ensitrelvir). Fourth, the conformational and dynamic flexibility of the simpler SLL-0197800 molecule is more balanced than that of the more complicated ensitrelvir molecule (see Figure B again), which makes SLL-0197800 having easier repositioning and better actions on the catalytic cavities and pockets of the targeted enzymes’ active sites . Fifth, the larger number of atoms (37 atoms) in case of the ensitrelvir molecule increases the chances of significant steric hindrances and repulsion forces upon approaching the enzymatic active sites in human than that in case of the small-volume SLL-0197800 molecule (only 27 atoms).…”

Discovery of Hybrid Thiouracil–Coumarin Conjugates as Potential Novel Anti-SARS-CoV-2 Agents Targeting the Virus’s Polymerase “RdRp” as a Confirmed Interacting Biomolecule

“…Additionally, the mutated RNA of SARS-CoV-2 has given rise to resistant and virulent novel variants, imposing a significant burden on the scientific community to develop successful medicines and vaccines. − Although existing vaccines and drugs can reduce the severity of the disease, there is some cause for concern about the efficacy of vaccines in the context of increasing numbers of mutations. − Despite many possible targets, the RdRp (nsp12) complex is responsible for RNA replication and represents an ideal target for innovative RdRp inhibitors. − The use of RdRp has been a crucial strategy for treating several viral infections, including hepatitis C (HCV), , dengue, , zika, , influenza, , etc. Based on structural disparities and the mode of action, RdRp inhibitors can be categorized into two groups: nucleoside/nucleotide analogues (NAs) and non-nucleoside/nucleotide analogues (NNAs). , These nucleoside analogues are transformed into active nucleoside triphosphates by cellular enzymes, which deceive and trick SARS-CoV-2 RdRp and then are incorporated into the strand to stop viral replication. ,, Some commonly used clinically approved repurposed SARS-CoV-2 nucleoside RdRp inhibitors used to decrease morbidity and mortality are Remdesivir and Molnupiravir. ,− Other nucleoside RdRp inhibitors include Favipiravir, Galidesivir, Ribavirin, Sofosbuvir, Azvudine, and Taroxaz-26. ,,− Meanwhile, non-nucleoside analogues (NNAs) disrupt viral replication by directly binding to the active site of RdRp, which is one of their benefits over NAs. , To date, only a few RdRp NNAs have been reported . Suramin, which is a NNA that inhibits SARS-CoV-2 RdRp, was tested in antiviral assays, and its mode of action was corroborated by a cryo-EM structure. , In addition, Lycorine, reported as a NNA, directly inhibits the activity of SARS-CoV-2 RdRp …”