Roger G Linington
|Division||Physical & Biological Sciences|
|Department||Chemistry & Biochemistry Department|
|Affiliations||Microbiology & Environmental Toxicology|
|Web Site||Linington Research Group|
|Office||Physical Sciences Building 346|
|Office Hours||By appointment|
|Campus Mail Stop||Chemistry|
Research InterestsMarine natural products continue to be a source of inspiration and innovation in many areas of biomedical science. The research pursued in our laboratory focuses on two main areas of interest in this arena; drug discovery for neglected infectious diseases, and the use of natural products as probes for biological systems. Within these two related areas we are interested in the discovery of novel therapeutics for diseases including malaria, TB and dengue fever; the identification of novel targets for drug intervention; the determination of specific protein function using small molecule probes and the concerted development of all of these ideas to push our initial drug leads from early-stage discovery to preclinical development.
Antimalarial drug discovery has been an area of research that has suffered from a lack of international attention over the last 30 years. The burden of this destructive disease on human health is immense with an estimated 515 million cases annually. The current resurgence of investigative effort in this area has led to a number of promising new developments including the falcipains and the 8-aminoquinolines however the progress of lead compounds from discovery to early- and late-stage development has been slow, and the identification of novel antimalarial therapies remains a serious challenge in global human health research. The availability of novel therapeutics with potent activity against resistant strains of the malaria parasite will provide healthcare professionals with vital new strategies for the treatment of both uncomplicated and complicated malarial infections. Our research group is engaged in the search for novel antimalarial lead compounds from marine microbes using a combination of orthogonal screening approaches, modern LC-MS based dereplication strategies, and chemical genetics-based methods for mode of action studies together to advance our lead compounds towards preclinical development.
Advances in our understanding of complex biological systems such as host-parasite interactions have highlighted a need for the development of methods for exploring individual protein function. The development of chemical biology and the use of small molecules as probes for biological systems is an emerging field in this arena. In an analogous fashion to the use of classical genetics techniques for determining protein function, chemical genetics can be used in either a forward or reverse sense to develop a more thorough understanding of the role of a protein of interest, or to identify proteins involved in the execution of an observed phenotypic response. In line with this idea, our research group is developing novel strategies for the use of natural products as probes for biological systems. Specifically we are interested in developing techniques for the systematic generation of libraries of tagged small molecules for use in sub-cellular localization studies, protein identification and the determination of protein-protein interactions for given target systems. This research aims to blend the biological relevance of natural product scaffolds with some of the modern developments in chemical probe design to produce bioactive compounds with utility as tools in a broad array of different areas of biochemistry, cell biology and molecular genetics.
Biography, Education and TrainingB.Sc. University of Leeds, UK
Ph.D. Univ of British Columbia, Canada
Selected PublicationsPeach, K. C.; Bray, W. M.; Shikuma, N. J.; Gassner, N. C.; Lokey, R. S.; Yildiz, F. H.; Linington, R. G. "An image-based 384-well high-throughput screening method for the discovery of biofilm inhibitors in Vibrio cholerae" Mol. Biosyst. 2011
Liu, X.; Beyhan, S.; Lim, B.; Linington, R. G.; Yildiz, F. H. "Identification and characterization of a phosphodiesterase that inversely regulates motility and biofilm formation in Vibrio cholerae" J Bacteriol. 2010, 192, 4541-4552.
Sanchez, L. M.; Lopez, D.; Vesely, B. A.; Della Togna, G.; Gerwick, W. H.; Kyle, D. E.; Linington, R. G. “Almiramides A-C: Discovery and Development of a New Class of Leishmaniasis Lead Compounds” J. Med. Chem., 2010, 53, 4187 - 4197.
Balunas, M. J.; Linington, R. G.; Tidgewell, K.; Fenner, A. M.; Urena, L.-D.; Della Togna, G.; Kyle, D. E.; Gerwick, W. H. “Dragonamide E, a Modified Linear Lipopeptide from Lyngbya majuscula with Antileishmanial Activity” J. Nat. Prod., 2010, 73, 60 - 66.
Peach, K. C.; Linington, R. G. “New Innovations for an Old Infection: Antimalarial Lead Discovery from Marine Natural Products during the Period 2003–2008” Future Medicinal Chemistry, 2009, 1, 593 – 617.
Ng, J.; Bandeira, N.; Liu, W.-T.; Ghassemian, M.; Simmons, T. L.; Gerwick, W. H.; Linington, R. G.; Dorrestein, P. C.; Pevzner, P. A. “Dereplication and De Novo Sequencing of Nonribosomal Peptides” Nat. Methods, 2009, 6, 596 – 599.
Liu, W.-T.; Ng, J.; Meluzzi, D.; Bandeira, N.; Gutierrez, M.; Simmons, T. L.; Schultz, A. W.; Linington, R. G.; Moore, B. S.; Gerwick, W. H.; Pevzner, P. A.; Dorrestein, P. C. "Interpretation of Tandem Mass Spectra Obtained from Cyclic Nonribosomal Peptides." Anal. Chem. 2009, 81, 4002
Linington, R. G.; Clark, B. R.; Trimble, E. E.; Almanza, A.; Ureña, L. D.; Kyle, D. E.; Gerwick, W. H. "Antimalarial Peptides from Marine Cyanobacteria: Isolation and Structural Elucidation of Gallinamide A" J. Nat. Prod., 2009, 72, 14
Linington, R. G.; Edwards, D. J.; Shuman, C. F.; McPhail, K. L.; Matainaho, T.; Gerwick, W. H. “Symplocamide A, a Potent Cytotoxin and Chymotrypsin Inhibitor from the Marine Cyanobacterium Symploca sp.” J. Nat. Prod., 2008, 71, 22-27.
Bandeira, N.; Ng, J.; Meluzzi, D.; Linington, R. G.; Dorrestein, P.; Pevzner, P. A. "De Novo Sequencing of Nonribosomal Peptides." Research in Computational Molecular Biology; Proceedings of the Twelfth Annual International Conference on Computational Molecular Biology (RECOMB 2008), 181 - 195.