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Home > Press > Small molecules hit it big - new therapeutic approaches against viruses, bacteria, and cancer: Scientists from Freie Universität Berlin have identified small molecule inhibitors of cellular uptake

Abstract:
Scientists from Freie Universität Berlin and the NeuroCure Cluster of Excellence led by biochemist Volker Haucke in collaboration with colleagues from Australia and the Leibniz Institute for Molecular Pharmacology (FMP) in Berlin have developed small molecules that inhibit the internalization of important signaling molecules but also of pathogenic organisms such as the immunodeficiency virus (HIV) and bacteria into cells. These compounds inhibit the function of the cellular scaffold protein clathrin und could thereby serve as a starting point for novel therapeutic approaches for the treatment of cancer, viral or bacterial infections, or neurological disorders. These results were published in the latest issue of the prestigious journal Cell.

Small molecules hit it big - new therapeutic approaches against viruses, bacteria, and cancer: Scientists from Freie Universität Berlin have identified small molecule inhibitors of cellular uptake

Berlin, Germany | Posted on August 6th, 2011

The uptake of important signaling molecules such as growth factors but also communication within the nervous system depends on the intracellular scaffold protein clathrin. Clathrin is involved in the production of small only about 100 nm sized vesicles (a nanometer equals as little as 1/billion meter). These vesicles shuttle signaling molecules into the cell interior or serve as storage sites for the triggered release of transmitter in the nervous system. The scientists used small molecule compound libraries comprising about 20,000 different substances paired with medicinal chemistry-based synthesis to identify small molecules that specifically inhibit binding of clathtrin to its partner proteins. These compounds termed pitstops are able to prevent within minutes the uptake of signaling molecules, which stimulate cell growth and division, or the entry of human immunodeficiency virus (HIV) into cells. Using shiny fluorescent proteins the scientists could identify impaired dynamics of clathrin and its partners as the underlying reason for the internalization block. "Vesicle formation appears stalled as if you had put your cells into the freezer," explains Professor Haucke. Similar effects have been observed in lamprey and in cultured nerve cells from mice or rats treated with pitstops resulting in a block in vesicle reformation and neurotransmission. As many neurological disorders, such as epilepsy are caused by overexcitability of nerve cells dampening of neurotransmission by pitstops and like substances could open new avenues for the therapy of these diseases. "Clathrin-mediated uptake into cells is of such fundamental importance that with the development of these inhibitors we might be able to devise new concepts for the treatment of so far incurable cancers such as brain tumors - tumors whose growth depends on the internalization of signaling molecules, which promote cell division," explains NeuroCure scientist Volker Haucke.

Full bibliographic informationRole of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition
Volker Haucke et al.
Cell, Volume 146, Issue 3, 471-484, 5 August 2011
The article on the web www.cell.com/current

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For more information, please click here

Contacts:
Kerrin Zielke


Prof. Dr. Volker Haucke
Institute of Chemistry and Biochemistry
Freie Universität Berlin
phone: +49-30/ 838–56922
e-mail:
www.fu-berlin.de/cellbio

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