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Oligooxopiperazines as Topographical Helix Mimetics

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Peptidomimetics II

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 49))

Abstract

Protein–protein interactions are often mediated by amino acid side chain functionality organized on secondary structures. Small molecule scaffolds that reproduce the array of protein-like functionality at interfaces offer an attractive approach to target therapeutically important interactions. Here, we describe the design, synthesis, and the biological potential of small molecule helix mimetics derived from an oxopiperazine scaffold to target protein complexes in which binding is largely dictated by one face of the interfacial helix. The oxopiperazine helix mimetics can be assembled from α-amino acids using standard solid-phase peptide synthesis methodology, enabling rapid diversification of the scaffold and discovery of ligands for protein targets. We have evaluated the biological potential of the oxopiperazine mimetics in cell-free, cell culture, and in vivo models. Our results support the hypothesis that the scaffold offers an attractive platform for the development of novel inhibitors of protein–protein interactions.

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Acknowledgments

We thank the National Science Foundation (CHE-1151554) for financial support of this work. The Rosetta computational analyses were performed by Kevin Drew and Richard Bonneau (NYU), while the effects of the designed compounds on the hypoxia-inducible signaling pathway were analyzed in collaboration with Ivan Grishagin and Bogdan Olenyuk (USC). We thank these long-term collaborators for their insights on these projects.

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  1. Department of Chemistry, New York University, New York, NY, 10003, USA

    Brooke Bullock Lao & Paramjit S. Arora

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  1. Brooke Bullock Lao
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  2. Paramjit S. Arora
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Correspondence to Paramjit S. Arora .

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  1. Départemente de Chimie, Université de Montréal Départemente de Chimie, MONTREAL, Québec, Canada

    William Lubell

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Lao, B.B., Arora, P.S. (2016). Oligooxopiperazines as Topographical Helix Mimetics. In: Lubell, W. (eds) Peptidomimetics II. Topics in Heterocyclic Chemistry, vol 49. Springer, Cham. https://doi.org/10.1007/7081_2015_195

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