This proposal aims to unravel three dimensional structures of the IdeR family of metal-dependent regulators of topoisomerases I of pathogenic organisms. Also the precise mode of action of a number of inhibitors of human topoisomerase I, called """"""""topo poisons"""""""", will be investigated. These include compthothecin derivatives recently introduced for the treatment of cancer. In addition, all three-dimensional structures available will be used for the design, synthesis and testing of new topo I poisons of human and pathogenic organisms, and the development of """"""""superactivators"""""""" of the IdeR family of regulators. We specifically aim to arrive at agents which modify the action of these proteins in such a manner that the damage to the cellular machinery will be greater than could be expected on the basis of """"""""mere"""""""" inhibition or activation of the DNA-binding proteins. This holds both for IdeR superactivators and topoisomerase I poisons which each aim to prolong the lifetime of the protein-DNA complexes targeted thereby involving collisions with replication forks and other entities on the DNA highway, leading to DNA damage and cell death. The four bacterial members of the IdeR family studied differ greatly with respect to DNA sequences recognized and metal ions used for activation. These include Mtb-IdeR from Mycobacterium tuberculosis, TroR from Treponema pallidum, SirR from Staphylococcus epidermis and DtxR from Corynebacterium diphtheriae. The human topoisomerase I structures solved recently by our group will initially be the major focus for structure-base inhibitor development. In later stages structures of topoisomerase I from the most important malaria parasite, Plasmodium falciparum, and of other major global parasites, will be explored for the development of anti-infectious agents. This project aims at developing better drugs for (i) the treatment of some of the mot difficult cancers, (ii) the most important infectious bacterial agent (M. tuberculosis), and (iii) the most devastating eukaryotic parasite (P. falciparum) known. The latter two account for roughly five million deaths per year worldwide.
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