KALAMAZOO, MI, United States

Aureogen Biosciences, Inc.

www.aureogen.com
KALAMAZOO, MI, United States
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ALQAISI A.Q.I.,University of Baghdad | MBEKEANI A.J.,Lower Mountjoy | LLORENS M.B.,Lower Mountjoy | ELHAMMER A.P.,Aureogen Biosciences, Inc. | DENNY P.W.,Lower Mountjoy
Parasitology | Year: 2017

Toxoplasma gondii is an obligate intracellular protozoan parasite of the phylum Apicomplexa, and toxoplasmosis is an important disease of both humans and economically important animals. With a limited array of drugs available there is a need to identify new therapeutic compounds. Aureobasidin A (AbA) is an antifungal that targets the essential inositol phosphorylceramide (IPC, sphingolipid) synthase in pathogenic fungi. This natural cyclic depsipeptide also inhibits Toxoplasma proliforation, with the protozoan IPC synthase orthologue proposed as the target. The data presented here show that neither AbA nor an analogue (Compound 20), target the protozoan IPC synthase orthologue or total parasite sphingolipid synthesis. However, further analyses confirm that AbA exhibits significant activity against the proliferative tachyzoite form of Toxoplasma, and Compound 20, whilst effective, has reduced efficacy. This difference was more evident on analyses of the direct effect of these compounds against isolated Toxoplasma, indicating that AbA is rapidly microbicidal. Importantly, the possibility of targeting the encysted, bradyzoite, form of the parasite with AbA and Compound 20 was demonstrated, indicating that this class of compounds may provide the basis for the first effective treatment for chronic toxoplasmosis. Copyright © Cambridge University Press 2017 This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.


Wuts P.G.M.,Kalexsyn Inc. | Simons L.J.,Kalexsyn Inc. | Metzger B.P.,Aureogen Biosciences, Inc. | Sterling R.C.,Aureogen Biosciences, Inc. | And 2 more authors.
ACS Medicinal Chemistry Letters | Year: 2015

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 μg/mL. The approach is readily adaptable to large-scale synthesis and industrial production. © 2015 American Chemical Society.


PubMed | Aureogen Biosciences, Inc. and Kalexsyn Inc.
Type: Journal Article | Journal: ACS medicinal chemistry letters | Year: 2015

The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 g/mL. The approach is readily adaptable to large-scale synthesis and industrial production.


Patent
Aureogen Biosciences, Inc. | Date: 2012-03-23

In general, the invention relates to methods of synthesizing AbA derivatives that are useful for treating infection and amenable to further chemical elaboration. These novel methods are scalable for industrial production and employ safer, simpler, and more efficient process conditions. Furthermore, the invention also provides novel compounds and intermediates useful for implementing the methods described herein and/or for the treatment of infection.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 481.48K | Year: 2011

DESCRIPTION (provided by applicant): The continuing increase in the number of surgery, transplantation, cancer and other immunocompromized patients, that need treatment for fungal infections, together with the fact that only one new class of antifungal therapeutics has been introduced to the market in over 30 years has created an immediate need for new and better antifungal drugs with novel modes of action (MoA). The natural product compound Aureobasidin A (AbA) is a potent, fungicidal drug with a novel MoA that also does not elicit resistant pathogen strains. Unfortunately, although efficacious and very well tolerated, native AbA's target spectrum is too narrow to be clinically attractive. Of the two major human pathogens, Candida spp. and Aspergillus spp., AbA only has efficacy against Candida. However, exploratory synthetic chemistry work has demonstrated that structural modifications can convert native AbA into compounds that have close to equal efficacy against both pathogens. The required chemistry, however, is complicated and expensive, to the extent that it constitutes a barrier against development of these compounds into commercial products. The overall goal of the project outlined in this proposal is to use a novel genetic engineering approach to introduce the structural modifications required to confer Aspergillus spp. activity to AbA, thereby avoiding the high cost of synthetic chemistry and allow commercialization of an efficacious, well tolerated antifungal drug with a novel MoA. In Phase I, the gene, aba 1, encoding the non-ribosomal peptide synthetase (NRPS) complex responsible for synthesis of AbA in the producer organism was identified, cloned, sequenced and mapped. Phase II has to date produced methodologies and a set of genetic tools thatallow efficient engineering of the aba 1 gene. Also accomplished to date is the successful engineering of the aba 1 gene, the generation of engineered strains producing structurally modified AbA molecules and the generation of significant new data on the unique properties of fungal NRPS complexes. Production of structurally altered cyclic peptides by engineering of a fungal NRPS complex has not been reported previously. The project has to date produced two publications, one issued patent and one pending patent application. The continued Phase II work will involve engineering of the specific modifications required to confer Aspergillus spp. activity to AbA and the preparation/selection of a producer strain capable of high production levels. Successful completion of the project will: [1] provide an efficient, well-tolerated drug to a market with a strong demand for new products; [2] address a very immediate need from a growing patient population which currently have very few treatment options; and [3] provideproof of concept and critical tools for a novel and potentially very powerful approach to the discovery of new and improved therapeutics. PUBLIC HEALTH RELEVANCE: The continuing increase in the number of surgery, transplantation, cancer and other immunocompromized patients, that need treatment for fungal infections, has generated an immediate unmet need for new antifungal drugs with novel modes of action. The proposed project will add a potent, efficacious, well-tolerated and economical drug to an inventory of antifungal drugs that currently is both limited and associated with significant limitations.


Aureogen Biosciences, Inc. | Entity website

Technology and Research About 70% of currently used drugs are natural products or derivatives of natural products. In contrast to synthetic compounds, natural product compounds are not generated by chemical synthesis, but instead isolated from living microorganisms, such as bacteria and fungi ...


Aureogen Biosciences, Inc. | Entity website

AureoGen News April 30, 2009 AureoGen receives a Michigan 50 Companies to Watch award from The Edward Lowe Foundation in association with the Michigan Economic Development Corporation, Michigan Small Business & Technology Development Center, Small Business Association of Michigan, the U.S ...


Aureogen Biosciences, Inc. | Entity website

AureoGen Funding: AureoGen has to date raised approximately $7.8 million from the following sources: $200,000 ...


Aureogen Biosciences, Inc. | Entity website

Mission Statement A number of successful drugs are natural products or derivatives of natural products. In contrast to synthetic compounds, natural products are not generated by chemical synthesis but instead isolated from microorganisms, such as bacteria and fungi ...


Aureogen Biosciences, Inc. | Entity website

Founders and Management AureoGen was founded by Ake Elhammer, Ph.D ...

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