Rachel Carson College Faculty Fellows

Summary of Expertise

Organic chemistry; combinatorial synthesis, biotechnology, molecular cell biology

Research Interests

Our mission is to create a new drug discovery paradigm that lies at the interface between conventional small molecules and biologics (e.g. antibodies and recombinant proteins). The drug discovery community has traditionally shied away from molecules in this size range (between ~500 and 10000 Da) because of the long-held perception that compounds with molecular weights much beyond 500 cannot cross cell membranes and therefore can’t be made orally bioavailable, that is, made into a pill. Further, molecules with low cell permeability are, by definition, incapable of acting on targets within the cell, limiting such molecules, including biologics, to injectable drugs against extracellular targets.

Modern “-omics” technologies such as shRNA, expression profiling, deep sequencing, and proteomics, have delivered vast datasets that biologists are beginning to mine for clues into the molecular basis of disease. As a result of these efforts, a wave of new candidate drug targets has emerged. Unlike typical enzymes and receptors, many of these new targets are signaling proteins and transcription factors whose functions are carried out through protein-protein or protein-DNA interactions. Since few of these biomolecules have conventional small molecule binding sites, finding cell permeable drugs that can modulate their functions presents one of the major challenges in drug discovery going forward. Medicinal chemists are now charged with the task of identifying molecular scaffolds that are large and complex enough to bind macromolecular interfaces, but yet have the membrane permeability associated with typical small molecule drugs.

Our laboratory studies membrane permeability in molecules whose structures violate classical predictors of “drug-likeness” (e.g. Lipinski’s “rule of five”) based on molecular weight and polarity. Many of these ”rule breakers” are natural products such as the cyclic peptide cyclosporine A (CSA), a highly effective immunosuppressive drug that is orally bioavailable despite its molecular weight of ~1200. We are investigating the physico-chemical properties of molecules like CSA and, using synthetic model systems, are uncovering interesting relationships between structure, conformation, and membrane permeability in these molecules.

Another major focus of the laboratory is the development of new methodologies for synthesizing “natural product-like” cyclic peptides. In collaboration with Prof. Matthew Jacobson at UCSF, we have developed robust computational methods for predicting membrane permeability in large cyclic peptides. Using a combination of synthetic and computational approaches, we are preparing large libraries of cyclic peptides whose structures are biased toward membrane permeability. We are screening these libraries in the UCSC Chemical Screening Center in a variety of phenotypic assays, from antimicrobial screens to image-based screens in human cancer cell lines, with the ultimate aim of identifying cell-permeable cyclic peptides with potent biological activities in multiple defined cell-based and in vitro systems.

Biography, Education and Training

Ph.D., University of Texas, Austin

Selected Publications

• Rand AC, Leung SSF, Eng H, Rotter CJ, Sharma R, Kalgutkar AS, Zhang Y, Varma MV, Farley KA, Khunte B, Limberakis C, Price DA, Liras S, Mathiowetz AM, Jacobson MP, Lokey RS. Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance. MedChemComm. Web Publication 16 Aug 2012.
• Zuckerman NB, Myers AS, Quan TK, Bray WM, Lokey RS, Hartzog GA, Konopelski JP. Structural determination of NSC 670224, synthesis of analogues and biological evaluation. ChemMedChem. 7, (2012) 761-765. PMID: 22378491.
• Johnson TA, Sohn J, Inman WD, Samarkand AE, Loveridge ST, Vervoort HC, Tenney K, Liu J, Ang KKH, Ratnam J, Bray WM, Gassner NC, Shen YY, Lokey RS, McKerrow JH, Boundy-Mills K, Nukanto A, Kanti A, Julistiono H, Kardono LBS, Bjeldanes LF, Crews P. Natural product libraries to accelerate the high-throughput discovery of therapeutic leads. J. Nat. Prod. 74, (2011) 2545-2555.
• Peach KC, Bray WM, Shikuma NJ, Gassner NC, Lokey RS, Yildiz FH, Linington RG. An image-based 384-well high-throughput screening method for the discovery of biofilm inhibitors in Vibrio cholerae. Mol. Biosyst. 4, (2011) 1176-1184.
• White TA, Renzelman CM, Rand AC, Rezai T, McEwen CM, Gelev VM, Turner RA, Linington RG, Leung SSF, Kalgutkar AS, Bauman JN, Zhang Y, Liras S, Price DA, Mathiowetz AM, Jacobson MP, Lokey RS. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat. Chem. Biol. 7, (2011) 810-817.
• Watts KR, Morinaka BI, Amagata T, Robinson SJ, Tenney K, Bray WM, Gassner NC, Lokey RS, Media J, Valeriots FA, Crews P. Biostructural features of additional jasplakinolide (jaspamide) analogues. J Nat Prod. 74, (2011) 341-351.
• Tamble CM, St. Onge RP, Giaever G, Nislow C, Williams AG, Stuart JM, Lokey RS. The synthetic genetic interaction network reveals small molecules that target specific pathways in Sacchromyces cerevisiae. Mol. Biosyst. 7, (2011) 2019-2030.
• Kapitzky L, Beltrao P, Berens TJ, Gassner N, Zhou C, Wüster A, Wu J, Babu MM, Elledge SJ, Toczyski D, Lokey RS, Krogan NJ. Cross-species chemogenomic profiling reveals evolutionarily conserved drug mode of action. Mol. Syst. Biol. 6, (2010) 1-14.
• Möller C, Melaun C, Castillo C, Diaz ME, Renzelman CM, Estrada O, Kuch U, Lokey RS, Mari F. Functional hypervariability and gene diversity of cardioactive neuropeptides. J. Biol. Chem. 285, (2010) 40673-40680.
• Robinson SJ, Morinaka BI, Amagata T, Tenney K, Bray WM, Gassner NC, Lokey RS, and Crews P. New Structures and Bioactivity Properties of Jasplakinolide (Jaspamide): Analogues from Marine Sponges. J. Med. Chem. 53, (2010) 1651-1661.
• Turner RA, Weber RJ, Lokey RS. Direct Conversion of Resin-Bound Peptides to C-Terminal Esters. Org. Lett. 12, (2010) 1852-1855.
• Woerhmann MH, Gassner NC, Bray WM, Stuart JM, Lokey RS. HALO384: A halo-based potency prediction algorithm for high-throughput detection of antimicrobial agents. J. Biomol. Screening. 15, (2010) 196-205.
• Inman WD, Bray WM, Gassner NC, Lokey RS, Tenney K, Shen YY, TenDyke K, Suh T. Crews P. A β-carboline alkaloid from the Papau New Guinea marine sponge Hyrtios reticulatus. J. Nat. Prod. 73, (2010) 255-257.
• Boot CM, Gassner NC, Compton JE, Tenney K, Tamble CM, Lokey RS, Holman TR, Crews P. Pinpointing pseurotins from a marine-derived Aspergillus as tools for chemical genetics using a synthetic lethality yeast screen. J. Nat. Prod. 70, (2007) 1672-1675.
• Seballos L, Richards N, Stevens DJ, Patel M, Kapitzky L, Lokey RS, Millhauser G, Zhang JZ. Competitive binding effects on surface-enhanced Raman scattering of peptide molecules. Chem. Phys. Lett. 447, (2007) 335-339.
• Turner RA, Oliver AG, Lokey RS. Click Chemistry as a Macrocyclization Tool in the Solid Phase Synthesis of Small Cyclic Peptides. Org. Lett. 9, (2007) 5011-5014
• Nehil MT, Tamble CM, Combs DJ, Kellogg DR, Lokey RS. Uncovering genetic relationships using small molecules that selectively target yeast cell cycle mutants. Chem. Biol. Drug Des. 69, (2007) 258-264.
• Schuresko LA, Lokey RS. A Practical Solid Phase Synthesis of Glu7-Phalloidin and Entry into Fluorescent F-Actin Binding Reagents. Angew. Chem. Int. Ed. 46, (2007) 3547-3549.
• Combs DJ, Lokey RS; Extended peptoids: a new class of oligomers based on aromatic building blocks. Tet. Lett. 48, (2007) 2679-2682.
• Gassner NC, Tamble CM, Bock JE, Cotton M, White KN, Tenney K, St.Onge RP, Proctor MJ, Giaever G, Davis RW, Crews, P, Holman TR, Lokey RS. Accelerating the Discovery of Biologically Active Small Molecules Using a High-Throughput Yeast Halo Assay. J. Nat. Prod. 70, (2007) 383-390.
• Ralifo P, Sanchez L, Gassner NC, Tenney K, Lokey RS, Holman TR, Valeriote FA, Crews P; Pyrroloacridine Alkaloids from Plakortis quasiamphiaster: Structures and Bioactivity. J. Nat. Prod. 70, (2007) 95-99.
• Rezai, T, Bock, JE, Vuong, Kalyanaraman K, C, Lokey RS*, Jacobson MP*. Conformational Flexibility, Internal Hydrogen Bonding, and Passive Membrane Permeability: Successful In Silico Prediction of the Relative Permeabilities of Cyclic Peptides. J. Am. Chem. Soc. 128, (2006) 14073-14080 (*Corresponding authors).
• Rezai T, Yu B, Millhauser GL, Jacobson MP, Lokey RS. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J. Am. Chem. Soc. 128, (2006) 2510-2511.
• Perlman ZE, Bock JE, Peterson JR, Lokey RS. Geometric Diversity Through Permutation of Backbone Configuration in Cyclic Peptide Libraries. Bioorg. Med. Chem. Lett. 15, (2005) 5329-5334.
• Simon RA, Schuresko L, Dendurkuri N, Goers E, Murphy B, Lokey RS. One-bead-one-compound library of end-capped dipeptides and deconvolution by microflow NMR. J. Combi. Chem. 7, (2005) 697-702.