Potential Anti-SARS-CoV-2 Prodrugs Activated by Phosphorylation and Their Role in the Aged Population

Abstract

The COVID-19 pandemic has flared across every part of the globe and affected populations from different age groups differently. People aged from 40 to 80 years or older are at an increased risk of morbidity and mortality due to COVID-19. Therefore, there is an urgent requirement to develop therapeutics to decrease the risk of the disease in the aged population. Over the last few years, several prodrugs have demonstrated significant anti-SARS-CoV-2 effects in in vitro assays, animal models, and medical practice. Prodrugs are used to enhance drug delivery by improving pharmacokinetic parameters, decreasing toxicity, and attaining site specificity. This article discusses recently explored prodrugs such as remdesivir, molnupiravir, favipiravir, and 2-deoxy-D-glucose (2-DG) and their implications in the aged population, as well as investigating recent clinical trials.

Keywords: 2-Deoxy-D-glucose (2-DG); aged population; favipiravir; molnupiravir; prodrug; remdesivir.

Scheme 1

Final synthetic steps of Remdesivir, developed by Gilead.

Scheme 2

(A) Synthesis of the adenosine nucleoside analog (9) developed by Gilead; (B) Synthesis of p-nitrophenolate 2-ethyl butyl-L-alaninate (12); (C) Final synthetic steps of Remdesivir, developed by Gilead.

Scheme 3

Synthesis of Molnupiravir. (A) The original synthetic route reported by Emory University used uridine as the starting material. (B) Potential synthetic route reported by Merck using ribose as the starting material.

Scheme 4

Synthesis of favipiravir. (A) Synthetic route developed by Toyama Company. (B) Potential synthetic route developed by Nippon Soda and Toyama Company.

Scheme 5

Synthesis of 2-Deoxy-D-Glucose.

Figure 1

Mechanism of action of Remdesivir. It is converted into its nucleotide form and then into GS-441524, which inhibits RdRp of SARS-CoV-2. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE-2, angiotensin-converting enzyme 2.

Figure 2

Mechanism of action of Molnupiravir. It is hydrolyzed to form NHC and then phosphorylated to form the nucleotide analog NHC-triphophate, which inhibits RdRp of SARS-CoV-2. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE-2, angiotensin-converting enzyme 2; C, cytidine triphosphate; G, guanosine triphosphate; M, N4-hydroxycytidine triphosphate.

Figure 3

Mechanism of action of favipiravir. It is phosphoribosylated to afford its active nucleotide analog, which inhibits RdRp of SARS-CoV-2. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE-2, angiotensin-converting enzyme 2; RdRP, RND-dependent RNA polymerase; gRNA, guide RNA.

Figure 4

Mechanism of action of 2-Deoxy-D-glucose. It is converted into its active form, 2-deoxy-D-glucose, which depletes cellular ATP. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE-2, angiotensin-converting enzyme 2; TCA, tricarboxylic acid cycle; ATP, adenosine triphosphate; S protein, spike protein.