Table 3. Inspirations for the Nucleoside/Nucleotide Analog Prodrug Design for COVID-19 Treatment^a.

prodrug type	examples	original indication	original target site	dosing route	major activation site	ideas for COVID-19 drug development and applications
ProTide	TAF	HBV/HIV	liver/PBMCs	oral	liver	Parenteral dosing is recommended in order to bypass the extensive first-passing effect in the liver; this may be helpful when the first phosphorylation is the rate-limiting step in the activation. Increasing the plasma stability may be favorable for pulmonary loading.
	sofosbuvir	HCV	liver
	PSI-353661
	GS-6620/GS-465124
	GS2
	remdesivir	Ebola virus	PBMCs	IV infusion
cyclic monophosphate prodrug	PSI-352938	HCV	liver	oral	liver	This may be not suitable for COVID-19 because their activating enzyme CYP3A4 is deficient in the lung.
	JNJ-54257099
l-valyl ester prodrug	valacyclovir	HSV	genital	oral	intestine and liver	It is possible to improve the oral bioavailability of parent nucleoside form, especially when the first phosphorylation is not the rate-limiting step in the activation; May be capable of targeting intestinal SARS-CoV-2.
	l-val-DAC	cancer	tumor
octanoate prodrug	laninamivir octanoate	influenza virus	lung	inhalation	lung	example of long-acting inhaled antiviral prodrug

^aPBMCs: peripheral blood mononuclear cells; HSV: herpes simplex virus.