[Babcock_Hall]

I looked at the structures of these two antiviral compounds.  They both have a derivative of phosphoric acid at the 5'-position of the ribose that is esterified with a phenyl group.  There is also an alanine that is joined to the phosphorus via the amino nitrogen of the alanine residue in a phosphoramidate linkage.  Finally the carboxylate end of alanine is esterified, either with isopropanol or a 6-carbon alcohol.

I am interested in the reasons for these choices.  The molecules are neutral, and I presume that this is to make them more membrane-permeable.  Having one phosphorus is at least reasonable if you want a triphosphate analog, although prodrugs without one phosphorus are known or even a ribose or deoxyribose ring.  But I am wondering about the choice of alanine.  Why an amino acid, and why that particular amino acid?

[rolnor]

They have probably tested many esters and amids before settling for this combination, I guess it makes the prodrug exactly as stable as is optimal. It should pass through the intestine and in to the liver where it is hydrolyzed to the free monophosphate.

[AWK]

https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01594

Full article online.

[hollytara]

I assume they interfere with RNA synthesis and therefore block the virus from proliferating. 

It is a tricky balance - stop viral RNA synthesis but try not to stop healthy cell RNA synthesis too much.

[pgk]

1). Alanine esterification increases lipophilicity and helps the prodrug absorption.
2). Alanine is a small amino acid and consequently, the prodrug derivative is not so bulky to delay/inhibit the prodrug absorption.

[Babcock_Hall]

That is an interesting article.  The reason for including the phosphorus (what will become the α-phosphorus of an analog of a nucleoside triphosphate) is that biological addition of the first phosphoryl group is the slowest process.  Apparently the phosphoramidates have been around for a while and are called ProTides.

From what I can gather elsewhere compounds such as these potentially have three means of working as antivirals.  One is by chain termination (stopping the polymerase); two is by causing an increasing number of mutations; and three is by inhibiting enzymes other than RNA-dependent RNA polymerase.  Remdesivir is a delayed chain terminator.  The polymerase adds a few more residues and then quits.
https://www.asbmb.org/asbmb-today/science/041020/slipping-past-the-proofreader

[pgk]

Mechanisms of action of remedsivir and sofosbuvir, respectively:
1). Mechanism of Inhibition of Ebola Virus RNA-Dependent RNA Polymerase by Remdesivir Viruses, 11(4), e-Article: 326, (2019)
https://www.mdpi.com/1999-4915/11/4/326
2). Efficiency of Incorporation and Chain Termination Determines the Inhibition Potency of 2′-Modified Nucleotide Analogs against Hepatitis C Virus Polymerase, Antimicrobial Agents and Chemotherapy, 58(7), 3636–3645, (2014)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068585/

[Babcock_Hall]

Some good reading there.  Thank you.