Prodrug Therapies for Infectious and Neurodegenerative Diseases

Abstract

Prodrugs are bioreversible drug derivatives which are metabolized into a pharmacologically active drug following chemical or enzymatic modification. This approach is designed to overcome several obstacles that are faced by the parent drug in physiological conditions that include rapid drug metabolism, poor solubility, permeability, and suboptimal pharmacokinetic and pharmacodynamic profiles. These suboptimal physicochemical features can lead to rapid drug elimination, systemic toxicities, and limited drug-targeting to disease-affected tissue. Improving upon these properties can be accomplished by a prodrug design that includes the careful choosing of the promoiety, the linker, the prodrug synthesis, and targeting decorations. We now provide an overview of recent developments and applications of prodrugs for treating neurodegenerative, inflammatory, and infectious diseases. Disease interplay reflects that microbial infections and consequent inflammation affects neurodegenerative diseases and vice versa, independent of aging. Given the high prevalence, personal, social, and economic burden of both infectious and neurodegenerative disorders, therapeutic improvements are immediately needed. Prodrugs are an important, and might be said a critical tool, in providing an avenue for effective drug therapy.

Keywords: HIV-associated neurocognitive disorders (HAND); SARS-CoV-2; drug derivatization; hepatitis; human immunodeficiency virus (HIV); infectious diseases; neurodegenerative disorders; prodrugs.

Figure 1

Bioconversion of levodopa (L-DOPA) prodrug to L-DOPA by enzyme carboxylesterases in the blood (case of XP21279). L-DOPA then passes through the blood-brain barrier (BBB) and permeates into the brain where it is converted to dopamine via DOPA decarboxylase. Created using BioRender.com (Accessed on 2 January 2022).

Figure 2

Mechanism for in vivo activity of LASER ART. (A) Intramuscular injection of cabotegravir prodrug nanoformulation (NM2CAB). (B) Lymphoid organs such as spleen act as secondary depots for the nanoformulation with internalization of NM2CAB by splenic macrophages. (C) The nanoformulation is slowly released from the macrophages and enters the extracellular matrix. (D) Dissolution of the nanocrystals provides free prodrug M2CAB. (E) Enzymatic hydrolysis and alkaline pH release the promoiety from the native drug. (F) The pharmacologically active native drug (CAB) enters the systemic circulation and elicits its activity as a potent integrase inhibitor. Created using BioRender.com (Accessed on 2 January 2022).