Porphyrin derivatives as versatile proteasome modulators

Abstract

The ubiquitin proteasome system (UPS) is the primary degradation system in eukaryotic cells, with high selectivity for a myriad of soluble proteins, and perturbations in the UPS are associated with numerous human disorders. For this reason the proteasome has become a pharmacological target for cancer and neurodegenerative diseases where opposite effects are desirable, inhibition and activation respectively. Interestingly, accumulation of the ubiquitin-conjugated proteins, which have been tagged for degradation, but not efficiently degraded have been observed at advanced age in many tissues. Similar phenomena have been observed in many diseases such as Alzheimer, Parkinson, and other neurodegenerative disorders. In-line with these data the efficiency of the UPS and the proteasome in particular decrease with age, which suggests a link between neurodegenerative diseases and UPS dysfunction. Ubiquitinylated protein accrual has also been observed in senescent cells (which accumulate with age) and maybe caused by dysfunction of the proteasome or the ubiquitinating/deubiquitinating machinery. It has been suggested that activation of the proteasome core might be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases, such as Alzheimer s and Huntington s disease. Therefore, stimulating proteasome activity seems to be very promising as a therapeutic strategy for this type of pathology. It is also known that multiple hallmarks of cancer such as replicative immortality, apoptosis resistance, and increased proliferation, are clearly dependent on the proteasome and UPS. For this reason proteasome inhibition is a very promising anti-cancer therapy yet there are very few drugs available for this use. It is known that cationic porphyrins behave as proteasome inhibitors and their potency depends on the number of positive charges. During this PhD study, we have worked towards a deeper understanding of the molecular mechanisms responsible for the interactions between proteasome and the tetra cationic porphyrin H2T4. Moreover, other porphyrin, porphyrinoid derivatives and bio-inspired molecules have been studied for their potential roles in modulating proteasome function. Surprisingly, the tetra anionic porphyrin H2TPPS has an unexpected activator quality on 20S proteasome in both cell based assays and purified 20S CP. From these studies emerge a new scenario where these macrocyclic molecules, thanks to their inhibitory action on the proteasome, are becoming increasingly rich multi-target molecules for oncological applications. This research has also uncovered novel porphyrin molecules capable of activating the proteasome suggesting that they are capable of not just inhibition but proteasomal modulation and, if correctly designed, they are able to interact with the electrostatic access code of proteasome s core particle allowing for biological activities.