Use of Lawesson's reagent in organic syntheses.

A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19.

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected 3'-fluoro-3'-deoxythymidine triphosphate and 3'-azido-3'-deoxythymidine triphosphate, which are the active forms of two other anti-viral agents, Alovudine and AZT (an FDA-approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

Nucleotide analogues as inhibitors of SARS-CoV Polymerase.

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3'-fluoro-3'-deoxythymidine triphosphate, 3'-azido-3'-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.

https://biorxiv.org/content/10.1101/2020.03.12.989186v1.full.pdf

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase.

Some phosphonic acid analogs as inhibitors of pyrophosphate-dependent phosphofructokinase, a novel target in Toxoplasma gondii.

Inhibitors of Viral Nucleic Acid Polymerases. Pyrophosphate Analogues

Investigations of phosphonates and related biophosphate analogues as inhibitors of viral nucleic acid polymerases are summarized. General syntheses of α-halo phosphonoacetic acid (PAA) and methanediphosphonic acid (MDP) derivatives have been extended to preparation of seven α-halo phenyl (phosphonomethyl) phosphinates (PhMpP). Two phosphonates containing potentially reactive α-keto groups, oxophosphonoacetate (phosphonoglyoxalate, COPAA) and oxomethanediphosphonate (carbonyldiphosphonate, COMDP) are discussed. A convenient, two-step synthesis of trisodium thiophosphonoformate (TPFA) from trimethyl phosphonoformate (Me3PFA) [via Me3TPFA) is presented. TPFA selectively inhibits HIV-1 reverse transcriptase (RT) relative to both human DNA polymerase α (pol α) and four herpesvirus DNA polymerases. The significance of membrane Na+/Pi cotransport inhibition by phosphonates is briefly addressed.

Design and Synthesis of Organophosphorus Compounds with Antiviral and Other Bioactivities

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Inhibitors of Viral Nucleic Acid Polymerases. Pyrophosphate Analogues

Design and Synthesis of Organophosphorus Compounds with Antiviral and Other Bioactivities

Design and Synthesis of Organophosphorus Compounds with Antiviral and Other Bioactivities