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Merging Synthetic Chemistry and Biology

Merging Synthetic Chemistry and Biology: A synthetic InsP8 Bound to the Kinase Domain of Human PPIP5K (collaboration with Steve Shears, NIH, USA)

Merging Synthetic Chemistry and Biology: A synthetic InsP8 Bound to the Kinase Domain of Human PPIP5K (collaboration with Steve Shears, NIH, USA)

« Why Nature Chose Phosphates » is the title of a Science classic article published in 1987 by Westheimer.[1] The initial statement « phosphate esters and anhydrides dominate the living world […] » spotlights the prominent importance of this type of modification. Phosphorylations of proteins, metabolites, cofactors and signaling molecules (such as inositides) are omnipresent in nature and tightly controlled by the actions of an impressively large set of kinases and phosphatases.[2] Since they lie at the very heart of cellular function, these enzymes have been identified as attractive drug targets in diverse pathologies such as cancer, Alzheimer’s, diabetes and obesity.[3] Research in the area of phosphorylated natural products clearly shows untapped potential and holds promise to decipher the enigmas of life. This is probably best documented in one of the last papers in 2009 by the late Nobel Laureate Arthur Kornberg on the structurally most simple representative, inorganic polyphosphate « Among our efforts to attract attention to Poly P, we have demonstrated the essential roles of Poly P in the virulence of major diseases, such as dysentery, tuberculosis, and anthrax, as well as in apoptosis, in the proliferative aspects of cancer, in osteoporosis, and in aging. The selection and conservation of Poly P in every cell in nature will ultimately survive the current neglect of its scientific study.»[4] Our research program is dedicated to the chemical synthesis of phosphorylated natural products and their analogues. Along the way, innovative phosphorylation methodology is developed and applied in the synthesis of densely phosphorylated natural products. One example is shown in the picture in which a synthetic InsP8 was soaked into the kinase domain of human PPIP5K, providing the first example of a non-natural inositol pyrophosphate analogue bound to a mammalian kinase. [5] Eventually, also such delicate compounds as Poly P will be obtained. Designed chemical probes will help us to understand, how these molecules interact with cellular components and will unveil new targets in drug discovery and development. Nature has chosen phosphates and their pervasiveness in life is calling for more vigorous efforts in the exploration of their potential.

[1] F. H. Westheimer, Science 1987, 235, 1173-1178.

[2] G. Manning, D. B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, Science 2002, 298, 1912-1934.

[3] a) D. Carling, Trends Biochem Sci 2004, 29, 18-24; b) M. H. Flight, Nat Rev Drug Discov 2013, 12, 739; c) J. Zhang, P. L. Yang, N. S. Gray, Nat Rev Cancer 2009, 9, 28-39.

[4] N. N. Rao, M. R. Gomez-Garcia, A. Kornberg, Annu Rev Biochem 2009, 78, 605-647.

[5] S. Capolicchio, H. Wang, D. T. Thakor, S. B. Shears, H. J. Jessen, Angew. Chem. Int. Ed. 2014, 53, 9508-9511.