Discovery of Novel Antifungal (1,3)-β-
            <scp>d</scp>
            -Glucan Synthase Inhibitors

Onishi, Janet C.; Meinz, María; Thompson, John R.; Curotto, James E.; Dreikorn, Sarah; Rosenbach, Mark; Douglas, Cameron M.; Abruzzo, George K.; Flattery, Amy; Kong, Li; Cabello, Angeles; Vicente, Francisca; Peláez, Fernando; Dı́ez, Maria Teresa; Martin, I.; Bills, Gerald F.; Giacobbe, Robert A.; Dombrowski, Anne W.; Schwartz, Robert E.; Morris, Sandra A.; Harris, Guy H.; Tsipouras, Athanasios; Wilson, Ken; Kurtz, Myra B.

doi:10.1128/aac.44.2.368-377.2000

Cited by 290 publications

(207 citation statements)

References 53 publications

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“…According to Juan, homoallylamines displays similar and stronger antifungal activity by inhibiting 1,3 β glucan synthase against Epidermophyton floccosum and Microsporum canis with amphotericin B and ketoconazole [29]. Onishi stated that lipopeptide antifungal agents are potential therapeutic agents against aspergillosis and candidiasis by inhibiting 1,3 β glucan synthase [30]. In this study also it was observed a good interaction between 1, 3 β glucan synthase with azadirachtin and the derivatives.…”

Section: Discussionmentioning

confidence: 49%

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Nagesh

Muniappan

Kannan

2018

Asian J Pharm Clin Res

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Objective: This study was aimed to inhibit the 1, 3 β-glucan synthase with azadirachtin or with the derivatives by docking method. Methods:The homology model of the protein 1, 3 β glucan synthase was prepared with "easy modellar" using query sequence and template and it was validated with procheck of Ramachandran plot. The ligand was selected from the PubChem database, and the .sdf file was downloaded which was converted to another file format with open babel. The .pdb files of protein and ligand were uploaded for rough docking with iGEMDOCK, and finally, the accurate docking was made with autodock vina. The docked poses were visualized with PYMOL then saved. The derivatives of the ligand were generated with SWISS ADME, free online software, and selected the derivative for docking. Results:The results obtained from iGEMDOCK and Autodock Vina were tabulated. It was found out that the Azadirachtin and the derivatives are effective in binding 1, 3 β Glucan synthase and thereby inhibiting the formation and integrity of fungal cell wall. Conclusion:In this study, the secondary metabolite Azadirachtin and the derivatives are showing inhibitory action against the model protein 1, 3 β glucan synthase and it was suggested that the external application of the ligand and its derivatives can be used because of their poor oral bioavailability.

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Section: Discussionmentioning

confidence: 49%

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Nagesh

Muniappan

Kannan

2018

Asian J Pharm Clin Res

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“…Enfumifungin represents a structurally distinct natural product class of GS inhibitors. Originally discovered in Merck by screening natural product extracts to which a S. cerevisiae fks1 heterozygote deletion mutant displayed hypersensitivity, enfumafungin and several related acidic terpenoids (ascosterocide, arundifungin, and ergokonin A) were identified (Onishi et al 2000). The current development candidate MK-3118 (Fig.…”

Section: Emerging Targets and Molecular Scaffoldsmentioning

confidence: 99%

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

Roemer

Krysan

2014

Cold Spring Harbor Perspectives in Medicine

441

353

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Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.

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“…10 Its documented clinical efficacy, associated with the lack of interactions with the majority of drugs used during the course of allogeneic stem cell transplantation, 11 may indicate Caspofungin as the best option to be used as a secondary prophylaxis in patients undergoing stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

Fabritiis

Spagnoli

Bartolomeo

et al. 2007

Bone Marrow Transplant

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Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program

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Discovery of Novel Antifungal (1,3)-β- d -Glucan Synthase Inhibitors

Abstract: The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Naturalproduct inhibitors of cell wall (

Cited by 290 publications

References 53 publications

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection

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