RESUMO
Invasive fungal infections represent a public health problem that worsens over the years with the increasing resistance to current antimycotic agents. Therefore, there is a compelling medical need of widening the antifungal drug repertoire, following different methods such as drug repositioning, identification and validation of new molecular targets and developing new inhibitors against these targets. In this work we developed a structure-based strategy for drug repositioning and new drug design, which can be applied to infectious fungi and other pathogens. Instead of applying the commonly accepted off-target criterion to discard fungal proteins with close homologues in humans, the core of our approach consists in identifying fungal proteins with active sites that are structurally similar, but preferably not identical to binding sites of proteins from the so-called "human pharmacolome". Using structural information from thousands of human protein target-inhibitor complexes, we identified dozens of proteins in fungal species of the genera Histoplasma, Candida, Cryptococcus, Aspergillus and Fusarium, which might be exploited for drug repositioning and, more importantly, also for the design of new fungus-specific inhibitors. As a case study, we present the in vitro experiments performed with a set of selected inhibitors of the human mitogen-activated protein kinases 1/2 (MEK1/2), several of which showed a marked cytotoxic activity in different fungal species.
Assuntos
Antifúngicos , Micoses , Humanos , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Candida/metabolismo , Proteínas Fúngicas/química , Domínio Catalítico , Fungos/metabolismoRESUMO
Inteins are invasive intervening sequences that perform an autocatalytic splicing from their host proteins. Among eukaryotes, these elements are present in many fungal species, including those considered opportunistic or primary pathogens, such as Candida spp. Here we reviewed and updated the list of Candida species containing inteins in the genes VMA, THRRS and GLT1 and pointed out the importance of these elements as molecular markers for molecular epidemiological researches and species-specific diagnosis, since the presence, as well as the size of these inteins, is polymorphic among the different species. Although absent in Candida albicans, these elements are present in different sizes, in some environmental Candida spp. and also in most of the non-albicans Candida spp. considered emergent opportunistic pathogens. Besides, the possible role of these inteins in yeast physiology was also discussed in the light of the recent findings on the importance of these elements as post-translational modulators of gene expression, reinforcing their relevance as alternative therapeutic targets for the treatment of non-albicans Candida infections, because, once the splicing of an intein is inhibited, its host protein, which is usually a housekeeping protein, becomes non-functional.
RESUMO
La reumatología continental se halla en una época de grandes y acelerados cambios a tono con el mundo actual, vinculados con el mejor conocimiento de los mecanismos patogénicos desde el nivel molecular, el impetuoso desarrollo de la ingeniería genética, los anticuerpos monoclonales, y desarrollo de la industria farmacéutica todo ello en consonancia con el descubrimiento de nuevos blancos terapéuticos y nuevas formas de dirigir las estrategias de diagnóstico y tratamiento para el adecuado manejo de las afecciones autoinmunes reumáticas
The continental rheumatology is in a time of great and rapid changes in tune with today's world, linked to the better understanding of the pathogenic mechanisms from the molecular level, the rapid development of genetic engineering, monoclonal antibodies, and development pharmaceutical industry all in keeping with the discovery of new therapeutics and new ways of running the diagnostic and treatment strategies for the proper management of rheumatic autoimmune conditions whites