A gyógyszerkutatás új irányzatai: hatékonyság és biztonságosság

Összefoglaló. A betegségek mögött meghúzódó biokémiai, sejtbiológiai változások molekuláris szintű megértése a korszerű gyógyszerkutatás alapját képezi. A kiválasztott biológiai célpont, leggyakrabban egy fehérje, működésének gátlásától vagy fokozásától azt reméljük, hogy elősegíti a gyógyulást. A hagyományos gyógyszerkutatási megközelítések molekuláris alapját a kiválasztott fehérjével való közvetlen kölcsönhatás jelentette. Ugyanakkor a sejten belüli molekuláris biológiai folyamatok részletesebb megértése több új megközelítést nyitott a gyógyszerkutatás számára. A közlemény ezeket a gyógyszerkutatási irányzatokat mutatja be, külön kitérve biztonságosságukra. Summary. Human diseases originate from and are accompanied by changes in the biochemistry of cells. The molecular level understanding of these deviations from normal functioning is key to the curing of the diseases, therefore a principal objective of drug discovery. The key-lock principle postulated by Emil Fischer serves well the understanding of most enzymatic processes and has been helping researchers both in academia and industry to discover new drugs. The binding of a small molecule to the target protein and inhibiting or activating its function is the basis for the efficient functioning of a long list of current drugs. Sometimes the desired biological effect comes from the selective action on a single protein, in other instances it is the combined effect on the working of several proteins. The appropriate selectivity profile is key to the safety and efficiency of the drug in both cases. The completion of the Human Genome Project, in parallel with a significant improvement in the performance of the analytical instrumentation, increased our molecular and systemic level understanding of diseases immensely. Analysis of the differences between healthy and diseased cells and tissues led to the identification of new targets, a lot of which are not classical enzymes but proteins exerting their effect through molecular interactions with other proteins or nucleic acids. Although these proteins were considered undruggable some decades ago, their disease modifying potential led to the discovery of new approaches and modalities to target them. The inhibition of protein-protein interactions, for example, requires the selective targeting of hydrophobic surfaces, sometimes with very high affinity. Drug candidates acting through this molecular mechanism are typically beyond the size of classical drugs that might complicate their development. Besides interacting directly with the protein of interest we might also impact its working through manipulating its quantity within the cell. Interference with the proteasomal degradation of cellular proteins, blocking its working, or hijacking it to selectively increase the degradation of our protein of choice are promising new modalities that are transitioning from research into clinical practice. Alternatively, one might also interfere with the transcriptional machinery. Selective blocking of the messenger RNA responsible for carrying the sequence information of the targeted protein by using so called antisense oligonucleotides, small interfering RNAs, or micro RNAs can result in a decreased synthesis of the protein. Appropriately designed oligonucleotides can also enhance protein synthesis or lead to an alteration of the sequence to synthesize for a given protein. Finally, we might also target the epigenetic regulatory machinery, which is in charge of unpacking the DNA double helix from its storage form and making it available for transcription. This interference typically leads to a more complex change, the parallel modulation of the level of several proteins at the same time.