Study of RNA components by the synthesis of small molecules

The proposed research is intended to exploit RNA as a pharmaceutical target by the synthesis of rationally designed small molecules as lead structures and could potentially result in the development of novel antibiotics.

The work initially focused on substrates that bind specifically to the ribonucleic acid (RNA) components of the bacterial ribosome, which is a validated target for many known antibiotics. Additionally, technologies currently used for the global analysis of protein function, exemplified by the biotin-small molecule conjugates, are explored for the identification of novel RNA components as potential targets for small molecule interactions with therapeutic significance. Finally, exploration of RNA’s tertiary structure will be performed by the synthesis of “dynamic libraries”, where the individual final products will be generated in the presence of the biological target, resembling the outcome of a natural selection. Our approach is expandable to other RNA-domains, like the GTPase associated domain in 23S rRNA, target of the antibiotic thiostrepton, the Dimerization Initiation Site (DIS) from HIV-1 genomic RNA, or the internal ribosome entry sites (IRES), which are important targets for the treatment of viral pathogens such as HIV, polio and hepatitis C.

This project represents an interdisciplinary approach, comprising of synthetic, spectroscopic, biological, and computational studies and is expected to elucidate the pharmacological profile of various RNA components and increase our understanding for their individual function.

Design and synthesis of selective VEGF-R2 inhibitors

Angiogenesis is the process by which new blood capillaries sprout from pre-existing blood vessels, and it is well recognized that angiogenesis is an important mechanism governing tumor growth and metastasis. The recent clinical success of Avastatin® has provided a proof of principle for the potential of anti-angiogenic cancer therapy with anti-vascular enthothelial growth factor (VEGF) agents. This dimeric glycoprotein interacts with two high-affinity transmembrane tyrosine kinase receptors, VEGF-R1 (originally Flt-1) and VEGF-R2 (or human KDR), and results in the proliferation of the endothelial cells and their development into new blood vessels.

One of the potential therapeutic approaches utilizes VEGF-R tyrosine kinase inhibitors that target the intracellular signal transduction. Within the last 5 years there has been considerable effort to produce selective VEGF-R inhibitors, therefore structures of several nanomolar binders of VEGF-R2 have been obtained. Computational chemistry analysis of these results resulted in the design, synthesis and biological evaluation of novel VEGF-R2 inhibitors from our laboratories.

Novel selective inhibitors of aminopeptidases that generate antigenic peptides

Endoplasmic Reticulum aminopepti-dases, ERAP1 and ERAP2, as well as Insulin Regulated aminopeptidase (IRAP) play key roles in antigen processing, and have recently emerged as biologically important targets for manipulation of antigen presentation. Taking advantage of the available structural and substrate-selectivity data for these enzymes, we have rationally designed and synthesized a new series of inhibitors that display low micromolar activity. The selectivity profile for these three highly homologous aminopeptidases provides a promising avenue for modulating intracellular antigen processing.

For additional information on all our projects see also