From a protein to pharmaceutical target

Current pharmacological approaches to identify target have strong molecular basis. Giving the important results of genome and proteome projects in understanding cell biology and biochemistry, also pharmaceutical research changes its approach and obtains great advantages from this new knowledge. Indeed, once identifying mutations in genes involved in particular diseases in the genome project, the role of proteins have been defined by the proteome project. Numerous proteins responsible of cancer, neurodegenerative disease, immune disease and so on have been studied in this way, obtaining important results in disease understanding.
The first step to treat one disease is knowing the pathological mechanism on its basis. Altered proteins could have a high activity, in this case we talk about gain of function mutations, or lower activity than normal, and so we talk about loos of function. In both cases, genetic alterations cause an impaired protein activity with deleterious consequences on cellular homeostasis. One protein acquires pharmacological significance when has a crucial role in disease arising. The common way to demonstrate the importance of one protein in pathogenesis is silencing or restoring it, in the case of gain or loss of function respectively. SiRNA approach is often used to silence proteins and analyse the effect of this lack in cellular system. The big advantage of siRNA is the selectivity: indeed, if siRNA is well designed, it’s possible to obtain complete depletion of the protein of interest without interfering with other cellular functions. So, this approach is safer than the use of chemical inhibitor because of the lack of collateral events. Furthermore, siRNA is applicable to every kind of protein even if their function has not been clarified yet. In the case of loss of function, it’s possible to restore protein function by transfecting cells with wild type version of the protein. Unfortunately, this system is not so theoretically universal like siRNA, because in the case of dominant negative mutation the normal protein function cannot be restored. Numerous animal models are available to confirm results obtained in cellular assays: knock out and knock in animals have been developed to simulate loss or gain of function, respectively. In summary, in cellular system we can define the role of a protein in the disease of interest and we can understand how it’s possible to modulate its functionality in order to restore normal homeostasis. Then, in animal model we can verify the consequences of proposed treatment in a whole organism. This is the way to transform a simple protein into pharmaceutical target. Basic studies on protein function are usually performed in public institution or universities, in some cases with the contribution of pharmaceutical sponsor that would have major benefits from research results. Otherwise, the presence of spin off or start up companies inside the university allows preserving the economic value of research for the institute. In this manner, research independency is guaranteed and also diseases which pharmaceutical companies are not strictly interested in, could be studied.