Final answer:
NCAAs such as diselenide-containing analogs or fluorinated tryptophan are used to enhance the efficacy or modify the physicochemical properties of peptide and protein drugs. Metabolic engineering and proteome-wide NCAA incorporation allow broad modification of proteins, granting them novel functionalities for therapeutic use.
Step-by-step explanation:
Examples of non-canonical amino acids (NCAAs) used in residue-specific manipulations include those that introduce modifications to enhance the efficacy of peptide and protein drugs or to modify their physicochemical properties. For instance, NCAA encoding can accelerate the development of drugs like alpha-selenoconotoxins, where converting cystine to diselenide prevents reduction by glutathione or serum albumin, thereby increasing drug efficacy. In another example, by replacing tryptophan (Trp) with fluorinated Trp variants like 4FTrp, 6FTrp, or 5FTrp, a graded increase in hydrophobicity can be achieved, which alters the peptide's interaction with its environment. These modifications can bolster a drug's therapeutic potential, ivy increasing its hydrophobicity, enhancing its charge or enabling click-chemistry for irreversible attachment to target sites.
Another method includes proteome-wide incorporation of NCAAs, where wild-type amino acids are replaced by NCAAs throughout the proteome. This can be accomplished by feeding auxotrophs with NCAAs or by metabolic engineering using NCAA precursors. For instance, E. coli capable of synthesizing L-ß-thieno[3,2-b]pyrrolylalanine ([3,2]Tpa), a tryptophan analog, when fed with such precursors, can generate mutants that utilize [3,2]Tpa. Such broad incorporations of NCAAs can provide significant benefits by stabilizing proteins or by granting novel functional properties beneficial in therapeutic applications.