1. Rethinking Remdesivir: Synthesis, Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs
- Author
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Aaron F. Carlin, Karl Y. Hostetler, Rachael N. McVicar, Xing-Quan Zhang, James R. Beadle, Joyce Murphy, Victoria I Smith, Robert T. Schooley, Rachel E McMillan, Alex E. Clark, Jialei Xie, Sandra L Leibel, Aaron F. Garretson, and Nadejda Valiaeva
- Subjects
Adenosine ,remdesivir ,Pharmacology ,Huh7.5 cells ,01 natural sciences ,chemistry.chemical_compound ,Cricetinae ,Prodrugs ,Pharmacology (medical) ,Induced pluripotent stem cell ,Caco-2 cells ,Lung ,Huh7.5 cells and PSC-derived human lung cells ,media_common ,0303 health sciences ,Alanine ,Pharmacology and Pharmaceutical Sciences ,Prodrug ,Lipids ,Infectious Diseases ,5.1 Pharmaceuticals ,Medical Microbiology ,Vero E6 cells ,Development of treatments and therapeutic interventions ,Infection ,Adenosine monophosphate ,Drug ,medicine.drug_class ,media_common.quotation_subject ,Remdesivir ,Remdesivir nucleoside ,Calu-3 cells ,Microbiology ,Antiviral Agents ,Article ,lipid prodrugs ,Vaccine Related ,03 medical and health sciences ,Rare Diseases ,Pharmacokinetics ,Biodefense ,remdesivir nucleoside ,antiviral agents ,medicine ,Animals ,Humans ,030304 developmental biology ,010405 organic chemistry ,business.industry ,SARS-CoV-2 ,Prevention ,PSC-derived human lung cells ,Stem Cell Research ,Adenosine Monophosphate ,COVID-19 Drug Treatment ,0104 chemical sciences ,Bioavailability ,Emerging Infectious Diseases ,Good Health and Well Being ,chemistry ,Vero cell ,Antiviral drug ,business ,Nucleoside - Abstract
Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of severe acute respiratory syndrome coronavirus 2 (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 plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2-infected cells. Potent orally bioavailable antiviral drugs for early treatment of SARS-CoV-2 infection are urgently needed, and several, including molnupiravir and PF-07321332, are currently in clinical development. 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 high oral bioavailability, stability in plasma, and simpler metabolic activation, new oral lipid prodrugs of RVn had submicromolar anti-SARS-CoV-2 activity in a variety of cell types, including Vero E6, Calu-3, Caco-2, human pluripotent stem cell (PSC)-derived lung cells, and Huh7.5 cells. In Syrian hamsters, oral treatment with 1-O-octadecyl-2-O-benzyl-glycero-3-phosphate RVn (ODBG-P-RVn) was well tolerated and achieved therapeutic levels in plasma above the 90% effective concentration (EC90) for SARS-CoV-2. The results suggest further evaluation as an early oral treatment for SARS-CoV-2 infection to minimize severe disease and reduce hospitalizations.
- Published
- 2020