Abstract
We show that substituting a single atom, O to S (amide to thioamide), in a peptide bond results in global restriction of the conformational flexibility in peptide macrocycles with minimal perturbation of the parent conformation. The van der Waals interactions between the C[double bond, length as m-dash]S group and the surrounding atoms are the major driving force in inducing the conformational restriction, resulting in well-defined structures of these cyclic peptides with static 3-D presentation of the pharmacophores. Utilizing this property of thioamides, we report the development of a superactive antagonist of pro-angiogenic αvβ3, αvβ5 and α5β1 integrins, which are responsible for cancer cell proliferation and survival. Using simple thio-scanning and spatial screening of a non-efficacious and conformationally flexible cyclic peptide, we could achieve a more than 105 fold enhancement in its efficacy in cellulo via a single O to S substitution. The developed peptide shows better efficacy in inhibiting the pro-angiogenic integrins than the drug candidate cilengitide, with a significantly enhanced serum half-life of 36 h compared to that of cilengitide (12 h). The long shelf-life, absence of non-specific toxicity and resistance to degradation of the thioamidated macrocyclic peptides in human serum suggest the promise of thioamides in markedly improving the affinity, efficacy and pharmacology of peptide macrocycles.
Highlights
In recent years, peptide macrocycles, as opposed to small molecules, have emerged as an extremely useful scaffold to target various extracellular and intracellular proteins.[1]
Conformational impact of thioamides on a cyclic peptide backbone To initially determine the conformational impact of thioamide substitution in peptide macrocycles, we synthesized a regioisomeric library of monothionated analogs of the parent cyclic peptide cyclo(–D-Ala–Ala4–), which is known to adopt a bII0-type and g-type turn (Fig. 1A).[14]
The g-type turn is in equilibrium between an open and a closed form (suggested by the low temperature coefficient of Ala5HN, which is indicative of intramolecular hydrogen bonding (Fig. 1B)) as demonstrated by Kessler and Marshall et al.[15]
Summary
Peptide macrocycles, as opposed to small molecules, have emerged as an extremely useful scaffold to target various extracellular and intracellular proteins.[1].
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