Stereoselective design of amino acid bioconjugates: targeting strategies and physicochemical optimization

Amino acid conjugates are progressively becoming popular as a potent tactic to enhance the pharmacological efficacy of drugs, especially in the areas of cancer and antimicrobial therapy. By taking advantage of the intrinsic biological attributes of amino acids, their conjugates facilitate drug stability, selective accumulation, and enhanced therapeutic efficacies. In particular, the structural analogy of amino acids to physiological substrates enables these conjugates to use solute carrier transporters, commonly overexpressed in tumour cells, which allow for targeted and effective drug delivery. This review considers how amino acid properties like chirality, hydrophobicity and steric bulk can be modulated to maximize drug conjugates. We emphasize important design aspects, such as selection of linkers and coupling reagents, and how these have an impact on drug release and biodistribution. Specific focus is given to d-amino acid, which increases proteolytic stability and bioactivity for both anticancer and antimicrobial uses, and to l-amino acid, which is responsible for receptor recognition, metabolic compatibility and amino acid decorated nanoparticle formulation. The existing drawbacks of antibody-drug conjugates (ADCs) and peptide-drug conjugates (PDCs) are immunogenicity, enzymatic degradation and poor tissue penetration. Amino acid conjugates provide a strong rationale with higher chemical versatility and potential for better pharmacokinetics and less toxicity. By harnessing the insights from chemistry, transporter biology and therapeutic design, this review presents a strategy for the creation of next-generation amino acid conjugates that bridge molecular accuracy to clinical utility.