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

Abstract

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. Here we discuss 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 in order to achieve the necessary rates for in vivo delivery to the target, efficacy, and ultimately, clinical translation.

Disrupting GPCR Complexes with Smart Drug-like Peptides

“…Different strategies to boost CPP protease resistance while preserving cell penetration efficiency have been developed [109]. One noteworthy approach is that afforded by cyclic versions of CPPs (CCPPs for short) such as cyclo Tat [110] or CPP12 [111].…”

Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery

“…This increased affinity can be rationalized due the larger interaction surfaces of those ligands as well as the greater number of library members of about 10 12 . In spite of their potency, peptide hits are rarely applied as immediate starting points for intra-cellular targets due to their low cell-penetration although some possibilities to tweak their properties in the desired direction exist [56]. Alternatively, the identified peptides offer insights for the rational design of small moelcules through extensive medicinal chemistry efforts, converting peptide hits into LMW compounds with the desired pharmacological properties that mimic the key interacting side chains [57,58].…”

Fighting the spread of antibiotic resistance with bacterial competence inhibitors

“…However, several CSP pherotypes exist 33 , so individual CSP inhibitors will not cover the entire CSP polymorphism spectrum. Furthermore, peptides typically do not have favourable PK/PD characteristics 34 , and it is not clear if in the nasopharynx environment where bacteria are embedded within biofilms, the CSP analogues (peptides of 17 amino acids and positively charged) are able to penetrate and interact with their target, ComD. To identify small-molecule, FDAapproved agents with favourable PK/PD characteristics that block pneumococcal competence, we screened a compound library of 1,280 drugs including antimicrobials (http://www.prestwickchemical.com), (Table S1).…”