Computational design of new more powerful and specific drugs for the treatment of severe mycoses of epidemiological relevance

Project Details

Description

The present project aims to design more powerful and specific drugs for the treatment of mycosis caused by histoplasma capsulatum and candida albicans, combining bioinformatic and experimental methodologies. histoplasmosis (hpm) is the most frequent systemic mycosis in america, caused by the dimorphic fungus histoplama capsulatum, which is acquired by the host through the inhalation route. in colombia, we do not have real epidemiological data, as it is not a notifiable disease, however, it is presumed that there may currently be ~ 10 million asymptomatic people who are infected with this fungus, but under conditions such as an hiv coinfection. (70%) or treatment with immunosuppressants and biological products, which weaken the host's immune system,they can suffer a significant increase in the burden of the disease, which is already observed in our population. specific treatment for hpm is indicated in all immunocompromised patients and in those with acute or chronic lung disease, progressive disseminated and in patients with occasional pulmonary and mediastinal complications. in the most severe cases of this mycosis, the administration of amphotericin b is recommended, which, although it has a broad spectrum of coverage and a potent fungicidal effect, has the adverse effects of an important renal toxicity and reactions to the infusion. on the other hand, for the milder clinical form of the disease, itraconazole is administered, which has good activity against the fungus, but triggers many drug interactions. further,the treatment lasts between 12 weeks and 24 months, which significantly increases not only the cost, but also the potential side effects.

Objective

Validate possible therapeutic targets in the phosphatidylinositol signaling pathway in fungi, and design more powerful and specific drugs for the treatment of severe mycoses of epidemiological relevance, combining bioinformatic and experimental tools.

Expected results

In the present project, the option of using proteins of the signaling pathway of phosphatidylinositol as molecular targets in fungi will be explored for the first time. 'we will carry out a broad bioinformatic study, for several types of fungi, with the aim of identifying possible drug binding sites (not only the active site) in the enzymes of the phosphatidylinositol signaling pathway, comparing them with the corresponding sites in the proteins homologous human, and thus producing a map of possible specific and "drugable" sites in these microorganisms.
StatusFinished
Effective start/end date27/12/1627/12/18

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