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

Abstract

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 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 ODBG-P-RVn was well tolerated and achieved therapeutic levels in plasma above the EC 90 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.

Broad-Spectrum In Vitro Antiviral Activity of ODBG-P-RVn: An Orally-Available, Lipid-Modified Monophosphate Prodrug of Remdesivir Parent Nucleoside (GS-441524)

“…In vivo , RDV is converted rapidly to RVn ( 4 – 7 ), which has 0.5 to 2 log 10 less activity than RDV against most of the viruses tested. In contrast, ODBG-P-RVn was stable in plasma for >24 h and reached therapeutic plasma levels (above the EC 90 for SARS-CoV-2) after oral administration of 16.9 mg/kg of body weight to Syrian hamsters; it also did not produce virologically significant levels of RVn ( 13 ). Thus, one would predict sustained in vivo antiviral activity with ODBG-P-RVn, without substantial generation of RVn, the less active metabolite, in plasma.…”

“…To develop an orally bioavailable form of remdesivir, we recently synthesized a 1- O -octadecyl-2- O -benzyl- sn -glycerylester (ODBG) lipid-modified monophosphate prodrug of RVn (ODBG-P-RVn) (C 40 H 62 N 5 O 9 P) ( Fig. 1A ), which demonstrated more favorable in vitro antiviral activity than RVn and RDV against SARS-CoV-2 in Vero-E6 cells ( 13 ).…”

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

“…Molnupiravir, a prodrug of the nucleoside derivative N4-hydroxycytidine, was developed as an anti-influenza drug and acts as an inhibitor of viral RNA replication by the induction of copying errors during replication [ 132 , 133 , 134 ]. Paxlovid is a prospective oral drug combination of PF-07321332 and Ritonavir, which blocks the activity of the SARS-CoV-2-3CL protease [ 135 , 136 ].…”

Oral Nirmatrelvir/Ritonavir Therapy for COVID-19: The Dawn in the Dark?

“…Vaccines are considered to be the most significant and effective advance against the COVID-19 pandemic [ 7 ]. In addition to vaccines, many new drugs have been investigated or approved for combating COVID-19, such as remdesivir, molnupiravir, and nirmatrelvir/ritonavir [ 7 , 8 , 9 , 10 , 11 ]. Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of SARS-CoV-2 infection.…”

“…Remdesivir (RDV; GS-5734) is currently the only FDA-approved antiviral drug for the treatment of SARS-CoV-2 infection. However, RDV must be administered intravenously, restricting its clinical use to patients with relatively advanced disease requiring hospitalization [ 8 ]. Molnupiravir, an inhibitor of RNA-dependent RNA polymerase, provided a 30% reduction in hospitalization or death compared with the placebo group in a phase III study enrolling non-hospitalized adults with mild to moderate COVID-19, and at least one risk factor for severe disease, within five days of symptom onset [ 10 , 11 ].…”