Cyclic Peptide breakthrough paves way for oral treatment of disease

Good news! Possibly a breakthrough!

"... Peptide therapeutics have inherent advantages: high potency and selectivity and good efficacy, safety, and tolerability. However, there are downsides ... Most peptide therapeutics are large molecules, degrade in the harsh environment of the gut and most often can’t cross cell membranes, necessitating their administration by injection. ..."

"... The research team targeted the enzyme thrombin, which is a critical disease target because of its central role in blood coagulation; regulating thrombin is key to preventing and treating thrombotic disorders like strokes and heart attacks.

To generate cyclic peptides that can target thrombin and are sufficiently stable, the scientists developed a two-step combinatorial synthesis strategy to synthesize a vast library of cyclical peptides with thioether bonds, which enhance their metabolic stability when taken orally. ..."

From the abstract:

"Cyclic peptides can bind challenging disease targets with high affinity and specificity, offering enormous opportunities for addressing unmet medical needs. However, as with biological drugs, most cyclic peptides cannot be applied orally because they are rapidly digested and/or display low absorption in the gastrointestinal tract, hampering their development as therapeutics. In this study, we developed a combinatorial synthesis and screening approach based on sequential cyclization and one-pot peptide acylation and screening, with the possibility of simultaneously interrogating activity and permeability. In a proof of concept, we synthesized a library of 8,448 cyclic peptides and screened them against the disease target thrombin. Our workflow allowed multiple iterative cycles of library synthesis and yielded cyclic peptides with nanomolar affinities, high stabilities and an oral bioavailability (%F) as high as 18% in rats. This method for generating orally available peptides is general and provides a promising push toward unlocking the full potential of peptides as therapeutics."

Peptide breakthrough paves way for oral treatment of disease Peptide therapeutics have revolutionized the treatment of disease, but their characteristics typically restrict them to administration by injection. Now, researchers have succeeded in creating an oral peptide, which has the potential to usher in a new era in drug development.

Oral peptides: A new era in drug development

De novo development of small cyclic peptides that are orally bioavailable (open access)

Fig. 1: Synthesis and metabolic stability of dithioether cyclic peptides.