Invited
The challenges in development of bioactive small molecules

Merck Israel R&D specializes in natural bioactive small molecule development and production for over 40 years. As such, we utilize divers natural resources such as bacteria, fungi and plants to extract and test various natural bioactive small molecules. Development and production of such molecules consist of multiple steps and can encounter various challenges along the way. Challenges could arise from the nature of the natural resource and its availability (bacteria, fungi, plant), the compound of interest nature (structure complexity, sensitivity to light, heat and air etc.) and regulations.

The nature of our work will be elucidated through three examples:

6,6′-Dihydroxythiobinupharidine - Is an active compound found in Nuphar lutea plant extract. It is a dimeric sesquiterpene thioalkaloid which presents multiple biological interesting activities; It was demonstrated to inhibit NFκB activation, leading to an induction of apoptosis via cleavage of procaspase-9 and poly (ADP-ribose) polymerase (PARP). In addition, 6,6′-Dihydroxythiobinupharidine was found to act synergistically with cytotoxic drugs and to possess antibacterial activity.

¹⁵N-Cyclosporin- A fungal metabolite possessing potent immunosuppressive properties by inhibition of the T-cell receptor signal transduction pathway. Cyclosporin is clinically used in organ transplantation procedures. Monitoring Cyclosporin blood level is highly important. We developed ¹⁵N-Cylosporin as a reference standardto monitor Cyclosporin levels in blood using LC-MS as a diagnostic tool in clinical testings.

MG-132 – A Synthetic short peptide analog that is related to as family of active proteasome inhibitors which eventually leads to apoptosis of cancer cells.