Aspartic Proteases of Human Pathogenic Fungi are Prospective Targets for the Generation of Novel and Effective Antifungal Inhibitors

Santos, André Luis Souza dos

doi:10.2174/157340811796575281

Cited by 18 publications

(15 citation statements)

References 235 publications

(243 reference statements)

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“…Other important mechanism of action is the inhibition of rhizopuspepsin and/or saps, a class of enzymes secreted for R. oryzae and other Rhizopus species [ 24 ]. The results in Figure 3 showed inhibition of proteolytic activity of rhizopuspepsin when Piper essential oils were used, mainly P. hispidum and P. tuberculatum which inhibited 11.8% and 12.05% of enzymatic activity, respectively.…”

Section: Resultsmentioning

confidence: 99%

Piper Essential Oils Inhibit Rhizopus oryzae Growth, Biofilm Formation, and Rhizopuspepsin Activity

Almeida

Azevedo

Chaves

et al. 2018

Canadian Journal of Infectious Diseases and Medical Microbiolog

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Piper is the largest genus of the Piperaceae family. The species of this genus have diverse biological activities and are used in pharmacopeia throughout the world. They are also used in folk medicine for treatment of many diseases in several countries including Brazil, China, India, Jamaica, and Mexico. In Brazil, Piper species are distributed throughout the national territory, making this genus a good candidate for biological activity screening. During our studies with Piper essential oils, we evaluated its activity against Rhizopus oryzae, the main agent of mucormycosis. The main compounds of seven Piper essential oils analyzed were Piper callosum—safrole (53.8%), P. aduncum—dillapiole (76.0%), P. hispidinervum—safrole (91.4%), P. marginatum—propiopiperone (13.2%), P. hispidum—γ-terpinene (30.9%), P. tuberculatum—(E)-caryophyllene (30.1%), and Piper sp.—linalool (14.6%). The minimum inhibitory concentration of Piper essential oils against R. oryzae ranged from 78.12 to >1250 μg/mL. The best result of total inhibition of biofilm formation was obtained with Piper sp. starting from 4.88 μg/mL. Considering the bioactive potential of EOs against planktonic cells and biofilm formation of R. oryzae could be of great interest for development of antimicrobials for therapeutic use in treatment of fungal infection.

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Section: Resultsmentioning

confidence: 99%

Piper Essential Oils Inhibit Rhizopus oryzae Growth, Biofilm Formation, and Rhizopuspepsin Activity

Almeida

Azevedo

Chaves

et al. 2018

Canadian Journal of Infectious Diseases and Medical Microbiolog

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“…In this context, proteolytic enzymes are promising targets for the action of new antifungal drugs, especially aspartic-type proteases that are implicated in several facets of basic biological processes of fungal cells as well as directly participating in numerous events of the interaction of fungal cells with host structures (Fig. 12) [250]. With this appeal, Saps of C. albicans fit these criterions because they are enzymes …”

Section: Discussionmentioning

confidence: 99%

Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis

Braga-Silva

Santos

2011

CMC

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Mycoses are still one of the most problematic illnesses worldwide, especially affecting immunocompromised individuals. The development of novel antifungal drugs is becoming more demanding every day, since existing drugs either have too many side effects or they tend to lose effectiveness due to the resistant fungal strains. In this scenario, Candida albicans is still the main fungal pathogen isolated in hospitals. Pathogenicity results essentially from modifications of the host defense mechanisms that secondarily initiate transformations in the fungal behavior. The pathogenesis of C. albicans is multifactorial and different virulence attributes are important during the various stages of infection. Some virulence factors, like the secreted aspartic proteases (Saps), play a role in several infection stages and the inhibition of one of the many stages may contribute to the containment of the pathogen and thus should help in the treatment of disease. Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs. Herein, we review the beneficial properties of pepstatin A and aspartic-type protease inhibitors used in the anti-human immunodeficiency virus chemotherapy on C. albicans, with particular emphasis in the effects on Sap activity, proliferation, morphogenesis (yeasts into mycelia transformation), ultrastructural architecture, adhesion to mammalian cells and abiotic materials, modulation of unrelated virulence factors (e.g., surface glycoconjugates, lipases and sterol), experimental candidiasis infection as well as synergistic properties when conjugated with classical antifungals. Collectively, these positive findings have stimulated the search for novel natural and/or synthetic pharmacological compounds with anti-aspartic protease properties against the human opportunistic fungus C. albicans.

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“…Currently, the main approach has been to obtain good inhibitors of the target protease, in the belief that inhibition of the activity will be therapeutic. In this context, our research group has published some works that corroborate this premise [1][2][3][4][5][6]10,[29][30][31][32][33][34][35][36][37][38][39] .…”

Section: Tripeptidyl Peptidases Dipeptidyl Peptidasesmentioning

confidence: 94%

“…Actually, C. albicans possesses ten different SAP genes (SAP1 to SAP10), which are expressed according to distinct environments and host conditions [56][57][58][59][60] . Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs [1,2,34,35] . In this context, several groups have demonstrated that aspartic protease inhibitors, including pepstatin A and the first generation of protease inhibitors used in anti-human immunodeficiency virus (HIV) therapy (nelfinavir, saquinavir, ritonavir and indinavir), are able to restrain Sap activity (especially Sap1, Sap2 and Sap3) as well as arrest crucial events of C. albicans yeast cells such as proliferation and adhesion to both abiotic (e.g.…”

Section: Tripeptidyl Peptidases Dipeptidyl Peptidasesmentioning

confidence: 99%

“…I am a peer reviewer for international scientific journals, as well as career and research grant committees. In addition, I have accepted invitations to write reviews and book chapters on the themes: (1) relevance of proteolytic enzymes produced by microorganisms; and (2) antimicrobial properties of protease inhibitors [1][2][3][4][5][6][7][8][9][10][11] . Over the last years, my group has focused on the identification, biochemical characterization and discovery of biological functions of proteases produced by microorganisms, with emphasis in trypanosomatids and fungi ( Figure 3).…”

Section: Introduction and Educational Experiencementioning

confidence: 99%

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Protease expression by microorganisms and its relevance to crucial physiological/pathological events

Santos¹

2011

WJBC

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The treatment of infections caused by fungi and trypanosomatids is difficult due to the eukaryotic nature of these microbial cells, which are similar in several biochemical and genetic aspects to host cells. Aggravating this scenario, very few antifungal and anti-trypanosomatidal agents are in clinical use and, therefore, therapy is limited by drug safety considerations and their narrow spectrum of activity, efficacy and resistance. The search for new bioactive agents against fungi and trypanosomatids has been expanded because progress in biochemistry and molecular biology has led to a better understanding of important and essential pathways in these microorganisms including nutrition, growth, proliferation, signaling, differentiation and death. In this context, proteolytic enzymes produced by these eukaryotic microorganisms are appointed and, in some cases, proven to be excellent targets for searching novel natural and/or synthetic pharmacological compounds, in order to cure or prevent invasive fungal/trypanosomatid diseases. With this task in mind, our research group and others have focused on aspartic-type proteases, since the activity of this class of hydrolytic enzymes is directly implicated in several facets of basic biological processes of both fungal and trypanosomatid cells as well as due to the participation in numerous events of interaction between these microorganisms and host structures. In the present paper, a concise revision of the beneficial effects of aspartic protease inhibitors, with emphasis on the aspartic protease inhibitors used in the anti-human immunodeficiency virus therapy, will be presented and discussed using our experience with the following microbial models: the yeast Candida albicans , the filamentous fungus Fonsecaea pedrosoi and the protozoan trypanosomatid Leishmania amazonensis .

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Aspartic Proteases of Human Pathogenic Fungi are Prospective Targets for the Generation of Novel and Effective Antifungal Inhibitors

Cited by 18 publications

References 235 publications

Piper Essential Oils Inhibit Rhizopus oryzae Growth, Biofilm Formation, and Rhizopuspepsin Activity

Piper Essential Oils Inhibit Rhizopus oryzae Growth, Biofilm Formation, and Rhizopuspepsin Activity

Aspartic Protease Inhibitors as Potential Anti-Candida albicans Drugs: Impacts on Fungal Biology, Virulence and Pathogenesis

Protease expression by microorganisms and its relevance to crucial physiological/pathological events

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