Assisting combinatorial biochemistry for new drug discovery

Macrocyclic compounds (epothilone, rifamycin and vancomycin) exhibit increased potential for developing new therapies against old and new diseases. In order to exploit the common functionalities that these compounds share, this EC funded project focused on adopting a biocatalytic combinatorial approach and developed advanced tools. For this reason, a new membrane process for filtering soluble polymers has also been developed that allows their increased purification and recovery during and after synthesis procedure.

Health

The wide use of antibiotics against infections has potentially caused the ineffective control of many diseases causing bacteria. Recently, it was found that macrocyclic compounds are sufficiently potent when used in treatment therapies against bacterial and fungal diseases as well as cancer. Moreover, these compounds display common activity and it is expected that if this is properly exploited, it may lead to the discovery of new improved drugs. Nevertheless, the appropriate combination of functionalities in macrocyclic structures has not been efficiently accomplished yet with tradional chemical methods used. Urged by this, the project concentrated on synthesising chemo- and bio-catalytic combinational libraries for screening purposes in various biological activities including generation of antibacterial and anticancer agents. Thereby, researchers developed innovative techniques for reactions on soluble high molecular-weighted polymers along with suitable enzymatically cleavable linkers, which offer release of compounds directly into assay mixtures. Supporting the syntnesis procedure, a new membrane process has been developed that allows ultra and nanofiltration of these soluble polymers in aqueous and organic solvents such as dichloromethane. This advanced process is well suited for purification of polymers such as polyethylenglycol (PEG) during the supported synthesis procedure and for their recovery after synthesis. Thus, it enables the extensive use of polymers that may exhibit advantages over insoluble carriers such as easier accessing reactive sites without seriously affecting the media during synthesis. Using commercially available ultra and nanofiltration membranes, it has showed high retention rates when recovering PEG derivatives with molecular weights of 5000g/mol. The membrane process is highly dependent on the combination of polymer and solvent used and despite some minor modifications it is readily available for wide applications. However, the selection of the most appropriate membrane along with its treatment for further use requires specialised know-how. Aiming for a scale-up method, the developers are currently working on resolving technical problems associated with larger filtration devices such as spirally wound modules in organic solvents.