(4) Cellular internalization of inorganic phosphate requires transporter proteins such as the phosphate: Na+ symporter family members (SLC20 and SLC34 Figure 1B). Inorganic phosphate cannot cross cell membranes by passive diffusion under physiological conditions. The cellular uptake of phosphates is relatively slow because these charged compounds have low rates of transmembrane diffusion. Some monoprotected and cyclic forms have been evaluated (not shown). These protecting groups may be symmetrical, asymmetrical or mixed ester/amide. Phosphoesters and phosphoamidates are typical prodrug components. (D) Some common forms of phosphonate prodrugs.
#BOBBY VALENTINO SLOW DOWN VK FREE#
Because prodrug diffusion is rapid and reversible, the rate of prodrug internalization is dependent upon irreversible bioconversion to the less diffusible free acid form. Charge-neutral prodrugs can more rapidly diffuse across cell membranes relative to their charged counterparts. ABCA1 can export endogenous isoprenoid diphosphates such as isopentenyl diphosphate (IPP). BPs enter cells from endosomes with the help of SLC37A3. Glucose 6-phosphate (G6P) can be imported to the ER by SLC37A4. Organic phosphate can be internalized by SLC20 and SLC34. The acidity of phosphates, phosphinates, phosphonates, and bisphosphonates (BPs) makes them negatively charged at physiological pH values.
(A) p K a values of common organophosphorus functional groups. Phosphates can cross the cellular membrane barrier with transporters or prodrug modifications. The structure–activity relationships described here will facilitate the rational design of future prodrugs.įigure 1. Through examining prior structure–activity studies on prodrug forms and the choices that led to development of remdesivir and other clinical drugs and drug candidates, a better understanding of their ability to distribute to the planned site of action, such as the liver, plasma, PBMCs, or peripheral tissues, can be gained. This review focuses on the role of metabolic activation in efficacy during oral and parenteral dosing of phosphate, phosphonate, and phosphinate prodrugs. The recent emergency use authorization of the antiviral remdesivir for COVID-19 exemplifies a new approach for delivery of phosphate prodrugs by parenteral dosing, which minimizes payload release during transit and maximizes tissue payload distribution. Despite decades of research on prodrug forms, choosing the ideal prodrug form remains a challenge which is often solved empirically. The ability to balance unwanted payload release during transit with desired release at the site of action is critical to prodrug efficacy. Effective prodrug forms distribute their payload to the site of the intended target and release it efficiently with minimal byproduct toxicity. Drugs that contain phosphates (and phosphonates or phosphinates) have intrinsic absorption issues and are therefore often delivered in prodrug forms to promote their uptake.