Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

Are peptides a solution for the treatment of hyperactivated JAK3 pathways?

While the inactivation mutations that eliminate JAK3 function lead to the immunological disorders such as severe combined immunodeficiency, activation mutations, causing constitutive JAK3 signaling, are known to trigger various types of cancer or are responsible for autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel diseases. Treatment of hyperactivated JAK3 is still an obstacle, due to different sensibility of mutation types to conventional drugs and unwanted side effects, because these drugs are not absolutely specific for JAK3, thus inhibiting other members of the JAK family, too. Lack of information, in which way sole inhibition of JAK3 is necessary for elimination of the disease, calls for the development of isoform-specific JAK3 inhibitors. Beside this strategy, up to date peptides are a rising alternative as chemo- or immunotherapeutics, but still sparsely represented in drug development and clinical trials. Beyond a possible direct inhibition function, crossing the cancer cell membrane and interfering in disease-causing pathways or triggering apoptosis, peptides could be used in future as adjunct remedies to potentialize traditional therapy and preserve non-affected cells. To discuss such feasible topics, this review deals with the knowledge about the structure-function of JAK3 and the actual state-of-the-art of isoform-specific inhibitor development, as well as the function of currently approved drugs or those currently being tested in clinical trials. Furthermore, several strategies for the application of peptide-based drugs for cancer therapy and the physicochemical and structural relations to peptide efficacy are discussed, and an overview of peptide sequences, which were qualified for clinical trials, is given.