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Peptoids and Peptide-Peptoid Hybrids

Macrocyclic peptoids offer advantages over some small molecule drugs because of their receptor selectivity, potency, and reduced off-target activity. Researchers from Pfizer, UC Santa Cruz, UCSF, and Circle Pharma have developed peptoid ligands that selectively bind receptor CXCR7.1 The chemokine receptor CXCR7 is a G-protein-coupled receptor recognized to have high affinity to ligand CXCL12 (know also as SDF-1). CXCL12 is known to stimulate B cell lymphopoiesis and bone marrow myelopoiesis.

Peptoid Chemistry

Ampocidin2 is an important natural product macrocycle that inhibits histone deacetylase (HDAC). HDAC inhibitors are promising therapuetic compounds for anticancer chemotherapy. Professor Ghadiri at The Scripts Resaerch Institute has developed a series of macrocyclic peptoid-peptide hybrides; one of which, selectively inhibits class I HDAC forms, but does not inhibit tubulin deacylase in class IIb HDAC6 (Figure below). In comparing the NMR structures of apicidin (left) to Ghadiri's peptoid-peptide hybrid (right), the distances between the pharmacophoric (molecular features required for molecular recognition) side chains are almost identical, despite the different cis-trans configurations of the amide bonds.

Apicidin peptoid-based peptidomimetics

Olsen, Christian A., Ana Montero, Luke J. Leman, and M. Reza Ghadiri. "Macrocyclic peptoid–peptide hybrids as inhibitors of class I histone deacetylases." ACS Medicinal Chemistry Letters 3, no. 9 (2012): 749-753.

Peptoid Molecular Diversity

The development of peptoid-based therapeutics offers a broad range of modular diversity due to the availability of synthetic building blocks. Compared to traditional alpha- and beta-peptides, peptoid-peptide hybrids provides access to distinct conformational spaces and diversity. Incorporating mixtures of peptide and peptoid residues into a sequence allows for the synthesis of oligomers and polymers with unique numbers of backbone atoms between side chains. The ability to vary distances between side chains combined with an extensive side chain diversity allows researchers to more easily modulate peptoid therapueitcs towards enhanced binding affinities, lower cytotoxicity, better solubility, and increased cell-permeability.

Optimized peptoid-peptide hybrids

Boehm, M., Beaumont, K., Jones, R.M., Kalgutkar, A.S., Zhang, L., Atkinson, K., Bai, G., Brown, J.A., Eng, H., Goetz, G.H. and Holder, B.R. "Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators." Journal of Medicinal Chemistry (2017).

Peptoid Literature

1. Boehm, M., Beaumont, K., Jones, R.M., Kalgutkar, A.S., Zhang, L., Atkinson, K., Bai, G., Brown, J.A., Eng, H., Goetz, G.H. and Holder, B.R. "Discovery of potent and orally bioavailable macrocyclic peptide-peptoid hybrid CXCR7 modulators." Journal of Medicinal Chemistry (2017).Learn More »

2. Olsen, Christian A., Ana Montero, Luke J. Leman, and M. Reza Ghadiri. "Macrocyclic peptoid–peptide hybrids as inhibitors of class I histone deacetylases." ACS Medicinal Chemistry Letters 3, no. 9 (2012): 749-753..Learn More »

In addition to changes in backbone periodicity for peptide-peptoid hybrids, peptoid residues can also expand into the space of cis-conformations, a configuration often absent in the typically trans amide bonds found in peptides and proteins.

Examples of Peptoid Building Blocks