Identification and Evaluation of Novel Drug Targets against the Human Fungal Pathogen Aspergillus fumigatus with Elaboration on the Possible Role of RNA-Binding Protein

Authors
Saeid Malekzadeh 1
Soroush Sardari 1
Parisa Azerang 1
Dorsa Khorasanizadeh 2
Solmaz Agha Amiri 2
Mohammad Azizi 2
Nazanin Mohajerani 2
Vahid Khalaj 2
1 Bioinformatics and Drug Design Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
2 Fungal Biotechnology Unit, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran 1316943551, Iran
10.18869/acadpub.ibj.21.2.84
Abstract
Bakground: Aspergillus fumigatus is an airborne opportunistic fungal pathogen that can cause fatal infections in immunocompromised patients. Although the current anti-fungal therapies are relatively efficient, some issues such as drug toxicity, drug interactions, and the emergence of drug-resistant fungi have promoted the intense research toward finding the novel drug targets. Methods: In search of new antifungal drug targets, we have used a bioinformatics approach to identify novel drug targets. We compared the whole proteome of this organism with yeast Saccharomyces cerevisiae to come up with 153 specific proteins. Further screening of these proteins revealed 50 potential molecular targets in A. fumigatus. Amongst them, RNA-binding protein (RBP) was selected for further examination. The aspergillus fumigatus RBP (AfuRBP), as a peptidylprolyl isomerase, was evaluated by homology modeling and bioinformatics tools. RBP-deficient mutant strains of A. fumigatus were generated and characterized. Furthermore, the susceptibility of these strains to known peptidylprolyl isomerase inhibitors was assessed. Results: AfuRBP-deficient mutants demonstrated a normal growth phenotype. MIC assay results using inhibitors of peptidylprolyl isomerase confirmed a higher sensitivity of these mutants compared to the wild type. Conclusion: Our bioinformatics approach revealed a number of fungal-specific proteins that may be considered as new targets for drug discovery purposes. Peptidylprolyl isomerase, as a possible drug target, was evaluated against two potential inhibitors and the promising results were investigated mechanistically. Future studies would confirm the impact of such target on the antifungal discovery investigations.
Keywords
Aspergillus fumigatus
RNA-binding protein
Peptidylprolyl isomerase
Juglone
RNA Interference