Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

Abstract

Recent tactical applications of prodrugs as effective tools in drug discovery and development to resolve issues associated with drug delivery of lead and drug candidates are reviewed as a reflection of the approval of 53 prodrugs during 2012–2022.

Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance

“…In this context, exploring antibacterial prodrugs is emerging as a promising strategy to combat bacterial AMR. Prodrugs can overcome the sub-optimal pharmacokinetic, biophysical, and physiochemical properties that limit drug efficacy [ 11 , 12 ]. These compounds may address bacterial resistance by introducing new drug properties, new modes of action and new drug targets, in line with the WHO criteria defined for the development of new antibacterial agents [ 7 ].…”

“…Prodrug development is emerging as a popular strategy to address the challenges encountered in drug development. Fifty prodrugs have been approved by the US Food and Drug Administration (FDA) between 2012 and 2022, indicating their growing acceptance [ 11 , 12 ]. This approach aims at mitigating issues such as the sub-optimal pharmacokinetic, biophysical, and physiochemical properties commonly found in drug candidates, including poor solubility, poor membrane permeability, chemical instability, and non-selective delivery, limiting their efficacy.…”

“…A prodrug is a compound that initially lacks pharmacological activity, becoming active through conversion into an active structure and non-toxic species upon intake. This type of drug can be classified into three classes: (i) carrier-linked prodrugs; (ii) bioprecursor prodrugs; and (iii) double prodrugs [ 11 , 12 , 13 ]. Modifying fundamental properties like polarizability, hydrophilicity, electronic and steric factors, hydrogen bonding, and chemical reactivity can yield the desired drug behavior [ 11 , 12 ].…”

“…Despite its promise, developing an ideal prodrug is challenging as it must meet several criteria without compromising final compound efficacy, including adequate aqueous solubility, optimal conversion rate, good safety profile, safe promoiety without undesirable side effects, rapid excretion, membrane permeability, and adequate stability. Moreover, although in vitro and in vivo assays have been developed over the years to evaluate the clinical potential of prodrugs, the development of these compounds is usually more complex and less predictable than for other drugs [ 11 , 12 ].…”

Single Molecular Nanomedicines Based on Macrocyclic Carrier-Drug Conjugates for Concentration-Independent Encapsulation and Precise Activation of Drugs

“…Traditional medicines act as a double-edged sword, offering potent therapeutic effects while often resulting in multiple undesirable side effects. − In the pursuit of augmenting therapeutic potential and mitigating adverse effects, researchers have developed various strategies, broadly categorized into two paradigms: one involves partial covalent modification of drugs, known as prodrugs; − the other entails noncovalent encapsulation of drugs to form nanomedicines, such as using liposomes, polymers, dendrimers, and other nanocarriers for drug delivery. − Rationally designed prodrugs or nanomedicines can to some extent enhance the drug’s solubility, stability, bioavailability, targeting, and reduce toxicity. − Additionally, they each have distinct advantages and disadvantages. Prodrugs possess clear structures and a single composition, thus exhibiting ease of production and good reproducibility, which is advantageous for clinical translation. − However, covalent modification only protects specific regions of drug molecules, often proving less effective in improving stability and reducing drug toxicity. , In contrast, nanomedicines formed through noncovalent interactions fully encapsulate and shield drug molecules. − Nevertheless, any nanomedicines based on noncovalent assemblies are inherently concentration-sensitive, potentially causing premature drug release during in vivo circulation, leading to nonspecific activation or introducing uncertainties in structure and complexity in pharmacokinetics upon assembly dissociation. − This multicomponent or multidispersed nature imposes significant limitations on the clinical translation of self-assembled nanomedicines. , Therefore, developing a novel strategy for targeted controlled drug release with explicit structure and simple composition while ensuring effective shielding of drug molecules in vivo and intrinsic concentration-independent properties holds important practical significance.…”