TROJA · Targeting Receptors Of Jointly Assembled Ligand-Drug Constructs

The TROJA proposal is an investigative bioengineering study of the exploitation of specific endocytic receptors for targeting small molecule drugs to specific cells in order to improve medical therapy. This is a new approach with scientific roots in the basic research on endocytic receptors and protein expression carried out in the laboratory of the applicant. The major line of the proposal concerns the construction of combinatory drugs for targeting the haptoglobin (Hp)-hemoglobin receptor CD163 (Kristiansen et al., Nature 409:198-201) expressed in the monocyte-macrophage system. The platform may apply to a broad spectrum of diseases such as inflammatory diseases, various infections and certain cancers which all have CD163-expressing macrophages or malignant derivatives as key cell type in the pathogenesis of the disease. Dependent of the above-mentioned diseases to be treated, the drugs are intended to have anti-inflammatory, microbiotic or cytostatic effects. Efficacy of the combinatory drug will be investigated in monocytes/macrophages, CD163-transfected cells and as well as in suitable animal models including transgenic animals. Another and minor line of the proposal concerns the construction of combinatory drugs for targeting a very recently discovered Hp-Hb receptor expressed in trypanosomes (Vanhollebeke et al., Science, in press) causing sleeping sickness. Both lines of this research proposal will take advantage of established recombinant protein expression methods and chemical coupling technology to construct jointly assembled ligand-drugs complexes. In terms of drug efficacy and toxicity, the aim is to design combinatory products that remain largely inactive in their receptor-binding form, but upon release in the cells or parasites the active small molecule components become active. The discovery of such a Trojan horse platform for cellular drug entry may have major implications for future drug development and for new applications of existent drugs.