Hitting Undruggable Targets: Viewing Stabilized Peptide Development through the Lens of Quantitative Systems Pharmacology

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 44; no. 3; pp. 241 - 257
• Main Authors: Atangcho, Lydia, Navaratna, Tejas, Thurber, Greg M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2019
• Subjects: alpha helices; Animals; cyclic peptides; Drug Design; Humans; lipophilicity; macrocycles; Peptides - chemistry; Peptides, Cyclic - chemistry; pharmacokinetics; stabilized peptides; cyclic peptides; pharmacokinetics; lipophilicity; macrocycles; alpha helices; stabilized peptides
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2018.11.008

Stabilized peptide therapeutics have the potential to hit currently undruggable targets, dramatically expanding the druggable genome. However, major obstacles to their development include poor intracellular delivery, rapid degradation, low target affinity, and membrane toxicity. With the emergence of multiple stabilization techniques and screening technologies, the high efficacy of various bioactive peptides has been demonstrated in vitro, albeit with limited success in vivo. We discuss here the chemical and pharmacokinetic barriers to achieving in vivo efficacy, analyze the characteristics of FDA-approved peptide drugs, and propose a developmental tool that considers the molecular properties of stabilized peptides in a comprehensive and quantitative manner to achieve the necessary rates for in vivo delivery to the target, efficacy, and ultimately clinical translation.
Stabilized peptides have the potential to hit currently ‘undruggable’ intracellular targets. However, reaching the cytosol remains one of the most challenging steps in delivery, and current knowledge of how physicochemical properties impact on membrane permeability is incomplete.
Strategies for cellular access, such as increasing lipophilicity or charge, impact on peptide distribution across multiple length-scales, including systemic plasma clearance, organ biodistribution, and tissue microdistribution (including heterogeneity from transient uptake or steady-state degradation).
Few clinical data are available, but several examples highlight modulation of lipophilicity as a means to improve clinical efficacy.
A systems approach to the quantitative pharmacology of stabilized peptides can improve translation by ensuring that in vitro properties are suitable for in vivo and clinical translation.