Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework.

Amanda Alves De Oliveira,Lívia Do Carmo Silva,Maristela Pereira,Carolina Horta Andrade,Bruno Junior Neves,Célia Maria De Almeida Soares

doi:10.3389/fmicb.2019.01301

Amanda Alves De Oliveira, Lívia Do Carmo Silva + Show 4 more

Open Access

https://doi.org/10.3389/fmicb.2019.01301

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Abstract

Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus Paracoccidioides and mainly affects low-income rural workers after inhalation of fungal conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and Paracoccidioides protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of Paracoccidioides spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Paracoccidioides essential targets using validated genes from Saccharomyces cerevisiae; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.

Highlights

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the saprobic and dimorphic Paracoccidioides species (ShikanaiYasuda et al, 2017)
We developed a computational chemogenomics framework (Figure 1) to repurpose drugs as anti-PCM bioactive using a genome-wide phylogenetic analysis of Pb01, Pb03 and Pb18 isolates
We have developed a computational chemogenomics framework to identify new anti-PCM drugs using the assumption that homologous proteins have enhanced probability of sharing the same ligands (Andrade et al, 2018)

Summary

Introduction

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the saprobic and dimorphic Paracoccidioides species (ShikanaiYasuda et al, 2017). Though a rare disorder from a global perspective, PCM is the most prevalent endemic mycosis in Latin America (Queiroz-Telles et al, 2017). Recent studies have shown that PCM is responsible for approximately half of deaths caused by systemic mycoses in Brazil (Martinez, 2017). The conidia transform into the pathogenic yeast in the lungs, triggering inflammatory responses, and formation of granulomatous lesions. The disease affects other tissues and organs, such as oral mucous membranes and skin. This disease has negative social and economic impacts, especially in individuals in their most productive phase of life (Shikanai-Yasuda et al, 2017)

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