Bruce E. Maryanoff, PhD

Distinguished Professor

Ph: (215) 589- 6411
Email: Bmaryano@scripps.edu

Training

Drexel University, Ph.D. in organic chemistry, (1972)
Princeton University, Postdoctoral Fellow in physical-organic chemistry, (1972-1974)

Appointment at the Blumberg: Distinguished Professor

Other appointments: Vice President and Professor of Chemical Biology, Pennsylvania Drug Discovery Institute; Visiting Scientist, The Scripps Research Institute, La Jolla, CA; Associate Editor, ACS Medicinal Chemistry Letters; Principal Member, Maryanoff & Maryanoff, LLC.

Research Overview

Dr. Maryanoff is currently conducting research involving self-assembling molecular systems, nanolipid particles as high-density lipoprotein (HDL)-mimetics to treat atherosclerosis, cyclic peptides that modulate the gastrointestinal microbiome, and histone deacetylase (HDAC) inhibitors. He serves as a consultant in the areas of drug discovery and chemical biology for numerous companies and institutes, as a member of numerous Editorial Advisory Boards, as an expert witness in pharmaceutical patent infringement cases, and as an Angel Investor in the Delaware Crossing Investment Group.

Research

Research: At The Scripps Research Institute since 2010, Dr. Maryanoff is collaborating closely with Prof. M. Reza Ghadiri and his group to perform research on (1) nanolipid particles as high-density lipoprotein (HDL)-mimetics for the prevention of atherosclerosis, (2) cyclic peptides as modulators of the gastrointestinal microbiome for the prevention of atherosclerosis, and (3) histone deacetylase (HDAC) inhibitors as modulators of epigenetic pathways, such as for applications to cystic fibrosis, spinal muscular atrophy (SMA), and cancer.

Area (1). Dr. Maryanoff has contributed to the molecular design, synthesis, and evaluation of apoA-I mimetic peptides that can form nanolipid discs and function as high-density lipoprotein (HDL)-mimetics. Dr. Maryanoff’s laboratory characterized promising nanolipid formulations by physical methods and biological assays. It performed bioassays in vitro and in cellular systems, and examined in vivo cholesterol lowering and pharmacokinetics in mice. Through chronic oral dosing in low-density lipoprotein (LDL)-null mice, his lab determined the efficacy of certain nanolipid formulations that significantly reduced plasma cholesterol and the aortic deposition of atherosclerotic plaque. Dr. Maryanoff was instrumental in establishing key research collaborations involving Prof. Linda Curtiss (Scripps), a biochemical pharmacologist, and scientists at Bristol-Myers Squibb (NJ), which also provided funding support, to propel this project forward.

Area (2). Dr. Maryanoff has contributed to exploring a supramolecular approach to find novel agents to treat atherosclerosis involving cyclic d,l-α-peptides, which can self-assemble into nanotube architectures and mimic the lipid binding and functional properties of apolipoprotein A-I (apoA-I). Certain 8-residue cyclic peptides promoted cholesterol efflux from macrophage cells and remodeled mature high-density lipoprotein (HDL) particles into nascent lipid-poor HDLs in vitro and in vivo. Oral administration of c[wLwReQeR] to low-density lipoprotein receptor (LDLr)-null mice fed a high-fat diet for 10 weeks reduced total plasma cholesterol levels by up to 55% and inhibited the development of atherosclerotic lesions in the aortic sinus by 50% (vs. controls). The mechanism of action appears to involve modulation of the gastrointestinal microbiome.

Area (3). Dr. Maryanoff has also contributed to the design, synthesis, and evaluation of histone deacetylase (HDAC) inhibitors based on macrocyclic tetrapeptides related to the natural product apicidin. Certain molecules were found to exhibit noteworthy activity in correcting the defective cystic fibrosis ion channel ΔF508-CFTR, which is responsible for ~90% of cystic fibrosis cases. He was instrumental in establishing a research collaboration between the Ghadiri lab and Prof. Elizabeth Winzeler (Scripps; UCSD), a malaria expert, to identify antimalarial HDAC inhibitors.

Research Summary

Medicinal Chemistry, drug discovery and development.

Selected Publications:

In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I. Y. Zhao, A. S. Black, D. J. Bonnet, B. E. Maryanoff, L. K. Curtiss, L. J. Leman, and M. R. Ghadiri, J. Lipid Res., 55, 2053-2063 (2014).

Mimicry of high-density lipoprotein: functional peptide-lipid particles based on multivalent peptide constructs. Y. Zhao, T. Imura, L. J. Leman, B. E. Maryanoff, and M. R. Ghadiri, J. Am. Chem. Soc., 135, 13414−13424 (2013).

Novel broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112). D. F. McComsey, V. L. Smith-Swintosky, M. H. Parker, E. Malatynska, D. Brenneman, H. S. White, B. D. Klein, K. S. Wilcox M. E. Milewski, M. Herb, M. F. A. Finley, Y. Liu, M. L. Lubin, N. Qin, A. B. Reitz, and B. E. Maryanoff, J. Med. Chem., 56, 9019-9030 (2013).

B. E. Maryanoff, J. C. O’Neill, D. F. McComsey, S. C. Yabut, D. K. Luci, A. D. Jordan, Jr., J. A. Masucci, W. J. Jones, M. C. Abad, A. Gibbs, and, I. Petrounia. Inhibitors of ketohexokinase: discovery of pyrimidinopyrimidines with specific substitution that complements the ATP-binding site. ACS Med. Chem. Lett., 2, 538-543 (2011).

Potential Agents for Treating Cystic Fibrosis: Cyclic tetrapeptides that restore trafficking and activity of ΔF508-CFTR. D. M. Hutt, C. A. Olsen, C. J. Vickers, D. Herman, M. Chalfant, A. Montero, L. J. Leman, R. Burkle, B. E. Maryanoff, W. E. Balch, and M. R. Ghadiri, ACS Med. Chem. Lett., 2, 703-707 (2011).

B. E. Maryanoff, L. de Garavilla, M. N. Greco, B. J. Haertlein, G. I. Wells, P. Andrade-Gordon, and W. M. Abraham. Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation. Am. J. Respir. Crit. Care Med., 181, 247-253 (2010).

E. C. Lawson, D. K. Luci, S. Ghosh, W. A. Kinney, C. H. Reynolds, J. Qi, C. E. Smith, Y. Wang, L. K. Minor, B. J. Haertlein, T. J. Parry, B. P. Damiano, and B. E. Maryanoff. Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits. J. Med. Chem., 52, 4958-4961 (2009).

R. J. Santulli, W. A. Kinney, S. Ghosh, B. L. DeCorte, R. A. Tuman, Z. Zhou, N. Huebert, S. E. Bursell, A. C. Clermont, M. B. Grant, L. C. Shaw, S. A. Mousa, R. A. Galemmo, Jr., D. L. Johnson, B. E. Maryanoff, and B. P. Damiano. Studies with an orally bioavailable av integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and in retinal vascular permeability in diabetic rats. J. Pharmacol. Exp. Ther., 324, 894-901 (2008).

M. A. Cejas, W. A. Kinney, C. Chen, J. G. Vinter, H. R. Almond, Jr., C. A. Maryanoff, K. Balss, M. Breslav, E. Lacy, and B. E. Maryanoff. Thrombogenic collagen-mimetic peptides: self-assembly of triple helix-based fibrils driven by hydrophobic interactions. Proc. Natl. Acad. Sci. USA, 105, 8525-8530 (2008).

M. A. Cejas, W. A. Kinney, C. Chen, G. C. Leo, B. A. Tounge, J. G. Vinter, P. P. Joshi, and B. E. Maryanoff. Collagen-related peptides: self-assembly of short, single strands into a functional biomaterial of micrometer scale. J. Am. Chem. Soc., 129, 2202-2203 (2007).

M. N. Greco, M. J. Hawkins, E. T. Powell, H. R. Almond, Jr., L. de Garavilla, J. Hall, L. K. Minor, Y. Wang, T. W. Corcoran, E. Di Cera, A. M. Cantwell, S. N. Savvides, B. P. Damiano, and B. E. Maryanoff. Discovery of potent, orally active, nonpeptide inhibitors of human mast cell chymase. J. Med. Chem., 49, 1727-1730 (2007).

M. J. Costanzo, H. R. Almond, Jr., L. R. Hecker, M. R. Schott, S. C. Yabut, H.-C. Zhang, P. Andrade-Gordon, T. W. Corcoran, E. C. Giardino, J. A. Kauffman, J. M. Lewis, L. de Garavilla, B. J. Haertlein, and B. E. Maryanoff. In-depth study of tripeptide ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1’ subsite and its implications to structure-based drug design. J. Med. Chem., 48, 1984-2008 (2005).

H.-C. Zhang, C. K. Derian, D. F. McComsey, K. B. White, H. Ye, L. R. Hecker, J. Li, M. F. Addo, D. Croll, A. J. Eckardt, C. E. Smith, Q. Li, W.-M. Cheung, B. R. Conway, S. Emanuel, K. T. Demarest, P. Andrade-Gordon, B. P. Damiano, and B. E. Maryanoff. Novel indolyl-indazolylmaleimides as inhibitors of protein kinase C-β: biological activity and cardiovascular safety. J. Med. Chem., 48, 1725-1728 (2005).

L. V. R. Boñaga, H.-C. Zhang, A. F. Moretto, H. Ye, D. A. Gauthier, J. Li, G. C. Leo, and B. E. Maryanoff. Synthesis of macrocycles via cobalt-mediated [2 + 2 + 2] cycloadditions. J. Am. Chem. Soc., 127, 3473-3485 (2005).

L. de Garavilla, M. N. Greco, N. Sukumar, Z.-W. Chen, A. O. Pineda, F. S. Mathews, E. Di Cera, E. C. Giardino, G. I. Wells, B. J. Haertlein, J. A. Kauffman, T. W. Corcoran, C. K. Derian, A. J. Eckardt, P. Andrade-Gordon, B. P. Damiano, and B. E. Maryanoff. A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo. J. Biol. Chem., 280, 18001-18007 (2005).