At Johnson & Johnson, my research group employed distinctly different approaches to discover new medicines. While we applied structure-based drug design to find potent enzyme inhibitors [J. Med. Chem. 2004  , 47, 769], sought antagonist ligands for various cell-surface receptors [Acc. Chem. Res. 2006  , 39, 831], and used phenotypic assessment [J. Med. Chem. 2009  , 52, 3431], we also traveled less conventional roads. Thus, we explored peptide derivatives in supramolecular modalities to seek potential drugs. One project involved collagen-model peptides that self-assembled to produce functional collagen-like materials. We designed and synthesized 32-mer peptides, (GPO)10 end-capped with aromatic amino acids, which formed triple-helical structures that self-assembled into micron-size, fibrillar, collagen-like materials [PNAS 2008  , 105, 8525]. Two 32-mers exhibited robust biofunctionality, as gauged by their induction of platelet aggregation in vitro. Another project involved mimetics of apolipoprotein A-I to produce reconstituted high-density lipoproteins for combating atherosclerosis. This research is now being pursued at Scripps-La Jolla in the laboratory of Prof. M. Reza Ghadiri. We designed, synthesized, and characterized novel, multivalent apoA-I mimetics and studied HDL-like nanoparticles generated from them. Our mimetics are based on molecular scaffolds bearing multiple, amphiphilic, alpha-helical peptides, the sequence of which was excerpted from apoA-I. The trimer construct (3 x 23-mers) was remarkably stable to proteolysis and had a prolonged half-life in mouse plasma in vivo. Phospholipid nanoparticles containing this substance functioned in vitro and in vivo to remodel mature HDL into nascent HDL and promote cellular cholesterol efflux. In LDL receptor-deficient mice, fed a high-fat diet, this nanomaterial robustly inhibited atherosclerosis in a 10-week, i.p.-dosing study.

Award Address  (E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances sponsored by Merck Research Laboratories). Seeking new drugs via unconventional drug discovery projects

245th National Meeting (2013)

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