From a CH to N swap to therapeutic prototypes to treat macular degeneration; modulation of the cluster of differentiation-36 receptor using azapeptides mediates macrophage-driven inflammation

In a peptide, exchange of the alpha-carbon for nitrogen in one amino amide gives a semicarbazide residue that may induce turn conformation and enhance metabolic stability [1]. Targeting the cluster of differentiation 36 receptor (CD36) to develop therapy to treat diseases featuring chronic inflammation, we have used such semicarbazides to prepare linear and cyclic azapeptides which exhibit improved selectivity and potency relative to their peptide ligand counterparts. On the surfaces of macrophages, CD36 serves as a scavenger for the recognition and phagocytosis of multiple-ligands [2]. Azapeptides can reduce CD36-mediated overproduction of nitric oxide, as well as proinflammatory cytokines and chemokines in macrophage cells after treatment with the Toll-like receptor-2-agonist fibroblast-stimulating lipopeptide [3,4]. Targeting treatments for dry age-related macular degeneration and atherosclerosis, azapeptide CD36 modulators have demonstrated therapeutic utility in mouse models of subretinal inflammation, coronary ligation and reperfusion [5].

Our presentation will describe synthetic methods, conformational analyses and biological assays to gain insight into the structure-activity requirements and to enhance the therapeutic potential of linear and cyclic azapeptide CD36 modulators for treating macrophage-driven inflammation.

1. Chingle, R.; Proulx, C.; Lubell, W.D. Acc. Chem. Res. 2017, 50, 1541-1556.
2. Silverstein, R.L.; Febbraio, M. Sci. Signal. 2009, 2, re3. doi: 10.1126/scisignal.272re3.
3. Possi, K.C.; Mulumba, M.; Omri, S.; Garcia-Ramos, Y.; Tahiri, H.; Chemtob, S.; Ong, H.; Lubell, W.D. J. Med. Chem. 2017, 60, 9263-9274.
4. Zhang, J.; Mulumba, M.; Ong, H.; Lubell, W. D. Angew. Chem. Int. Ed. Engl. 2017, 56, 6284-6288.
5. Huynh, D.N.; Bessi, V.L.; Ménard, L.; Piquereau, J.; Proulx, C.; Febbraio, M.; Lubell, W.D.; Carpentier, A.C.; Burelle, Y.; Ong, H.; Marleau, S. FASEB J. 2017, in press, doi: 10.1096/fj.201700505R.

Professor William Lubell

Professor William D. Lubell has been actively advancing the fields of medicinal chemistry and peptide science through the development of seminal methods to create and employ peptide and peptidomimetic prototypes that target and modulate biologically relevant receptors for drug discovery. Recipient of a B.A. from Columbia College (1984) and Ph.D. from the University of California, Berkeley (1989), where he studied under the supervision of Professor Henry Rapoport, Lubell was a Japan Society for the Promotion of Science Fellow (1990-1991) in the laboratory of Professor Ryoji Noyori at Nagoya University, Japan, before joining the Department of Chemistry at the Université de Montréal in 1991.

Co-author of over 250 scientific publications, Associate Editor of Organic Letters since 2005, editorial board member of journals in peptide science and drug design, and innovator of intellectual property to launch the Canadian start-up companies Mperia Therapeutics and Rytvel Biotech, his honors include the Boehringer Ingelheim Young Investigator Award, the DuPont Canada Educational Aid Grant, the Danish National Bank Award, the Merck Therapeutic Research Award, the 2013 CSC Bernard Belleau Award for achievements in medicinal chemistry, and in 2018, the Teva Canada Limited Biological and Medicinal Chemistry Lectureship Award.

Originator of Molecules of Life, Lubell explores experiential education techniques to teach elementary school students about molecules.

Seminar host: Dr Karl Hansford