个人简介

B.Sc. University of Leeds, UK Ph.D. Univ of British Columbia, Canada Postdoc UCSD and the Smithsonian Tropical Research Institute, joint appointment

研究领域

Marine Natural Products, Drugs for Neglected Diseases, Chemical Biology, Chemical Probes

Marine 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.

近期论文

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Kurita, K. L.; Linington, R. G.* “Connecting Phenotype and Chemotype: High-Content Discovery Strategies for Natural Products Research” Journal of Natural Products, 2015, ASAP. Schulze, C. J.‡; Navarro, G.‡; Ebert, D.‡; DeRisi, J.*; Linington, R. G.* “Salinipostins A−K, Long-Chain Bicyclic Phosphotriesters as a Potent and Selective Antimalarial Chemotype” Journal of Organic Chemistry, 2015, 80, 1312-1320. León, B.‡; Navarro, G.‡; Dickey, B. J.; Stepan, G.; Tsai, A.; Jones, G. S.; Morales, M. E.; Barnes, T.; Ahmadyar, S.; Tsiang, M.; Geleziunas, R.; Cihlar, T.; Pagratis, N.; Tian, Y.; Yu, H.; Linington, R. G.* “Abyssomicin 2 Reactivates Latent HIV‐1 by a PKC- and HDAC- Independent Mechanism” Organic Letters, 2015, 15, 262-265. Warner, C. J. A; Cheng, A. T.; Yildiz, F. H.; Linington, R. G.* “Development of benzo[1,4]oxazines as biofilm inhibitors and dispersal agents against Vibrio cholerae” ChemComm, 2015, 51, 1305-1308. Schulze, C. J.; Bray, W. M.; Loganzo, F.; Lam, M.-H.; Szal, T.; Villalobos, A.; Koehn, F.; Linington, R. G.* “Borrelidin B: Isolation, Biological Activity, and Implications for Nitrile Biosynthesis” J. Nat. Prod., 2014, 77, 2570-2574. Donia, M.; Cimermancic, P.; Schulze, C. J.; Wieland Brown, L. C.; Martin, J.; Makedonka, M.; Clardy, J.; Linington, R. G.; Fischbach, M. A.* “A Systematic Analysis of Biosynthetic Gene Clusters in the Human Microbiome Reveals a Common Family of Antibiotics” Cell, 2014, 158, 1402-1414. Cimermancic, P.; Medema, M. H.; Claesen, J.; Kurita, K.; Wieland Brown, L. C.; Mavrommatis, K.; Pati, A.; Godfrey, P. A.; Koehrsen, M.; Clardy, J.; Birren, B. W.; Takano, E.; Sali, A.; Linington, R. G.; Fischbach, M. A.* “Insights into Secondary Metabolism from a Global Analysis of Prokaryotic Biosynthetic Gene Clusters” Cell, 2014, 158, 412-421. Schulze, C. J. and Linington, R. G. (2014) ""Image-Based Screening Approaches to Natural Products Discovery."" In A. Osbourn, R. Goss & G.T. Carter (Eds.) Natural Products: Discourse, Diversity, and Design (pp. 373-396) New York, NY: Wiley. Higginbotham, S.*; Wong, W. R.; Linington, R. G.; Spadafora, C.; Iturrado, L.; Arnold, E. A.""Sloth Hair as a Novel Source of Fungi with Potent Anti-Parasitic, Anti-Cancer and Anti-Bacterial Bioactivity."" PLoS ONE 2014 9(1): e84549. doi:10.1371/journal.pone.0084549 Duncan, M. C.; Wong, W. R.; Dupzyk, A. J.; Bray, W. M.; Linington, R. G.; Auerbuch V.* ""An NF-κB-based high throughput screen identifies piericidins as inhibitors of the Yersinia pseudotuberculosis type III secretion system."" Antimicrob. Agents Chemother. 2014, 58, 1118-1126. Navarro, G.; Cheng, A. T.; Peach, K. C.; Bray, W. M.; Bernan, V. S.; Fitnat H. Yildiz, F. H.; Linington R. G.* ""An Image-Based 384-Well High-Throughput Screening Method for the Discovery of Skyllamycins A - C as Biofilm Inhibitors and Inducers of Biofilm Detachment in Pseudomonas aeruginosa"" Antimicrob. Agents Chemother. 2014, 58, 1092-1099. Liu, W.-T.; Lamsa, A.; Wong, W. R.; Boudreau, P. D.; Kersten, R.; Peng, Y.; Moree, W. J.; Duggan, B. M.; Moore, B. S.; Gerwick, W. H.; Linington, R. G.; Pogliano, K.; Dorrestein, P. C. ""MS/MS-based networking and peptidogenomics guided genome mining revealed the stenothricin gene cluster in Streptomyces roseosporus"" The Journal of Antibiotics 2014, 67, 99-104.