Protein engineering holds the potential to transform the metabolic drug landscape through the development of smart, stimulusresponsive
drug systems. Protein therapeutics are a rapidly expanding segment of Food and Drug Administration approved drugs that will
improve clinical outcomes over the long run. Engineering of protein therapeutics is still in its infancy, but recent general advances in protein
engineering capabilities are being leveraged to yield improved control over both pharmacokinetics and pharmacodynamics. Stimulus-
responsive protein therapeutics are drugs which have been designed to be metabolized under targeted conditions. Protein engineering
is being utilized to develop tailored smart therapeutics with biochemical logic. This review focuses on applications of targeted drug neutralization,
stimulus-responsive engineered protein prodrugs, and emerging multicomponent smart drug systems (e.g., antibody-drug conjugates,
responsive engineered zymogens, prospective biochemical logic smart drug systems, drug buffers, and network medicine applications).
Keywords: Biochemical logic, drug buffer, engineered zymogen, network medicine, protein engineering, stimulus-responsive, targeted drug
activation, targeted drug neutralization.
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