A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Abstract

As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide‐based drug candidates, drawing upon series of examples to illustrate each strategy.

Cyclic Peptide Extracts Derived From Pseudostellaria heterophylla Ameliorates COPD via Regulation of the TLR4/MyD88 Pathway Proteins

“…More than 40 cyclic peptide drugs have been clinically approved, the most of which are derived from natural world. But some cyclic peptides there are problems with the metabolic stability and oral absorption limits their development as drug candidates (Jing and Jin, 2020).…”

Structure-tuned membrane active Ir-complexed oligoarginine overcomes cancer cell drug resistance and triggers immune responses in mice

“…Articial modications such as lipidation, cyclization and stereoisomerisation are oen required to overcome the shortcomings inherent to peptides, including their natural hydrophilicity, structural instability and proteolytic vulnerability. [23][24][25][26][27][28][29] Meanwhile, a notable class of membrane-targeting cyclometalated iridium(III) complexes, have gained increasing attention because of their biomolecular reactivities and potent anticancer activities of novel mechanisms. [30][31][32][33][34][35][36][37] In this work, these two classes of membrane active compounds are bioconjugated to remove their respective disadvantages; for example, the iridium complex contributes to the peptide structural stability and enables luminescence-based analysis, whereas peptides endow the iridium complex with a suitable solubility.…”

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

“…Many of these attempts used cyclization as the method of choice to metabolically stabilize the peptides while preserving their natural activity. Cyclization strategies such as side chain-to-side chain cyclization as well as headto-tail cyclization and ring-closing olefin metathesis were used to synthesize opioid cyclic peptide analogs (Li et al, 2016;Remesic et al, 2016;Nielsen et al, 2017;Stefanucci et al, 2017;Bedini and Spampinato, 2018;Machelska and Celik, 2018;Weltrowska et al, 2019;Jing and Jin, 2020;Shinbara et al, 2020). Screening libraries of these cyclic peptides produced biologically active compounds with significantly improved chemical and biological stability, but also proved that there is a major effect of the cyclization method and ring size on the biological activity.…”