XI International Meeting on Paracoccidioidomycosis

XI International Meeting on Paracoccidioidomycosis

Resume:124-1

Investigação

124-1	Post-genomics and antifungal development
Authors:	Maria Sueli Felipe (UNB - Universidade de Brasilia)

Abstract

The prevalence of invasive fungal infections (IFIs) has increased steadily worldwide in the last few decades. IFIs have historically been associated with high morbidity and mortality, partly because of the limitations of available antifungal therapies, including side effects, toxicities, drug interactions and antifungal resistance. The search for alternative therapies and/or the development of more specific drugs is a challenge that needs to be met. In silico analyses and manual mining selected initially 57 potential drug targets, based on 55 genes experimentally confirmed as essential for C. albicans or A. fumigatus and other 2 genes (kre2 and erg6) relevant for fungal survival within the host. Orthologs for those targets were also identified in eight human fungal pathogens (C. albicans, A. fumigatus, B. dermatitidis, P. brasiliensis, P. lutzii, C. immitis, C. neoformans and H. capsulatum). Of those, 10 genes were present in all pathogenic fungi analyzed and absent in the human genome. We focused on four candidates: trr1 that encodes for thioredoxin reductase, rim8 encoding for a protein involved in the proteolytic activation of a transcriptional factor in response to alkaline pH, kre2 that encodes for α-1,2-mannosyltransferase and erg6 that encodes for Δ(24)-sterol C-methyltransferase. Of the four selected potential targets obtained, only Trr1 and Kre2 showed a reasonable sequence identity to the templates found in PDB. Also, we performed the homology modeling to predict 3D protein models only for these two proteins. To investigate the stability of Trr1 and Kre2 models, molecular dynamics simulations were performed and revealed that the evolution of the systems is very stable. With the models stable, virtual screening for select the main small molecules that interact with them was performed. A bank of commercially available compounds was docked with the models by virtual screening simulations. Small molecules that interact with the models were ranked and, among the best hits, 37 and 20 molecules were finally selected as putative inhibitors of Kre2 and Trr1, respectively. Our data show that the comparative genomics analysis of eight fungal pathogens enabled the identification of new potential drug targets conserved among fungi and absent in the human genome. Also, virtual screening of combinatorial libraries offered new perspectives on technological development and innovation of antifungal agents against human pathogens. Funding-FAP/DF,CNPq਀

Keyword: comparative genomics, post-genomic analysis, antifungal development

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