Dataset Information

Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity.

ABSTRACT: The FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells.

SUBMITTER: Schooley RT

PROVIDER: S-EPMC7457622 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs.

Schooley Robert T RT Carlin Aaron F AF Beadle James R JR Valiaeva Nadejda N Zhang Xing-Quan XQ Clark Alex E AE McMillan Rachel E RE Leibel Sandra L SL McVicar Rachael N RN Xie Jialei J Garretson Aaron F AF Smith Victoria I VI Murphy Joyce J Hostetler Karl Y KY

bioRxiv : the preprint server for biology 20210607

Remdesivir (RDV, GS-5734) is currently the only FDA-approved antiviral drug for the treatment of SARS CoV-2 infection. The drug is approved for use in adults or children 12-years or older who are hospitalized for the treatment of COVID-19 on the basis of an acceleration of clinical recovery for inpatients with this disease. Unfortunately, the drug must be administered intravenously, restricting its use to those requiring hospitalization for relatively advanced disease. RDV is also unstable in pl ...[more]

PMID: 32869033

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Project description:The double-stranded DNA (dsDNA) viruses represented by adenovirus and monkeypox virus, have attracted widespread attention due to their high infectivity. In 2022, the global outbreak of mpox (or monkeypox) has led to the declaration of a Public Health Emergency of International Concern. However, to date therapeutics approved for dsDNA virus infections remain limited and there are still no available treatments for some of these diseases. The development of new therapies for treating dsDNA infection is in urgent need. In this study, we designed and synthesized a series of novel disulfide-incorporated lipid conjugates of cidofovir (CDV) as potential candidates against dsDNA viruses including vaccinia virus (VACV) and adenovirus (AdV) 5. The structure-activity relationship analyses revealed that the optimum linker moiety was C2H4 and the optimum aliphatic chain length was 18 or 20 atoms. Among the synthesized conjugates, 1c exhibited more potency against VACV (IC50 = 0.0960 μM in Vero cells; IC50 = 0.0790 μM in A549 cells) and AdV5 (IC50 = 0.1572 μM in A549 cells) than brincidofovir (BCV). The transmission electron microscopy (TEM) images revealed that the conjugates could form micelles in phosphate buffer. The stability studies in the GSH environment demonstrated that the formation of micelles in phosphate buffer might protect the disulfide bond from glutathione (GSH) reduction. The dominant means of the synthetic conjugates to liberate the parent drug CDV was by enzymatic hydrolysis. Furthermore, the synthetic conjugates remained sufficiently stable in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and pooled human plasma, which indicated the possibility for oral administration. These results indicated 1c may be a broad-spectrum antiviral candidate against dsDNA viruses with potential oral administration. Moreover, modification of the aliphatic chain attached to the nucleoside phosphonate group was involved as an efficient prodrug strategy for the development of potent antiviral candidates.

Dataset Information

Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity.

Publications

Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs.

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