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KALAMAZOO, MI, United States

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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.98M | Year: 2006

DESCRIPTION (provided by applicant): There is an immediate need for novel drugs for the treatment of fungal infections, (antibiotics resistant) bacterial infections, and cancer. Cyclic peptides constitute a class of compounds that have made crucial contributions to the treatment of these diseases. Although cyclic peptides can be very efficient drugs, they are complex natural products and as such, difficult and expensive to optimize with conventional, chemistry- based methodologies. Currently used compounds are either native or native with minor modifications. Hence, the full potential of cyclic peptides for the treatment of human diseases has not been explored. The overall goal of the project is to develop a cost-effective production system for a novel antifungal drug. This molecule is a cyclic peptide and although it is both potent and well-tolerated, it requires structural modifications that cannot be introduced in a cost-effective manner by synthetic chemistry, to become a marketable product. Thus, the project involves development of methodologies and a set of genetic tools that will allow introduction of the required modifications by engineering of the non-ribosomal peptide synthetase (NRPS) complex responsible for synthesis of the molecule, in the producer organism. In Phase I, the gene encoding this NRPS complex was identified, cloned, sequenced and mapped. Phase II will involve modifying this gene such that the resulting, engineered organism will produce a drug molecule(s) with the properties required for a marketable product. Notably, successful engineering of the (NRPS gene in the) producer organism will allow production of this drug molecule at a fraction of the cost of synthetic chemistry thereby ensuring the successful commercialization of a potent, cidal antifungal drug with a novel mode of action. Successful generation of the engineered drug producer organism 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] provide proof of concept and critical tools for a novel and potentially very powerful genetic engineering approach to the discovery of new and improved therapeutics.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2008

DESCRIPTION (provided by applicant): HCV infections are a prevalent and growing health problem. It is estimated that as many as 2% of the US population, and 2.5% of the population world-wide, are infected by HCV. The disease currently causes 15,000 deaths/ year in US alone, a number that is predicted to increase three-fold by 2010. Treatment options for HCV infected patients are quite limited, and none of the currently available treatments has a better than 50% probability of eliminating the infection from t he patient. Consequently, there is a significant, and immediate unmet medial need for new and better drugs for the treatment of HCV infections. The cyclic peptides constitute a class of compounds that have made crucial contributions human health. These com pounds have a considerable presence in several therapeutic areas, ranging from infectious diseases, to cancer and even autoimmune disorders. The discovery of the immunomodulatory cyclic peptide Cyclosporin A (CsA) 50 years ago had a truly profound impact a nd literally ushered in the era of modern transplantation medicine. Although cyclic peptides often are very efficient drugs, they are also complex natural product molecules (isolated from bacteria and fungi) and as such, they are difficult and expensive to synthesize and/or modify with conventional, synthetic chemistry-based methodologies. Consequently, currently used cyclic peptide-based drugs are either native compounds or native compounds with minor modifications. The vast majority of these compounds hav e not been optimized for human use and, consequently, the full potential of cyclic peptides, as human therapeutics, has not been explored. The overall goal of the project outlined in this proposal is to use a novel genetic engineering approach that allows cost-effective generation and production of both modified and new cyclic peptides, to generate new and improved anti-HCV drug candidates. The established immunomodulatory drug CsA, a compound with a wide range of pharmacological activities that includes an ti-HCV activity, will be used as engineering template. The project involves development of methodologies and a set of genetic tools that allows introduction of modifications to the structure of native CsA by engineering the non-ribosomal peptide synthetase (NRPS) complex responsible its synthesis, in the producer organism Tolypocladium inflatum. Successful implementation of the envisioned genetic engineering approach will not only allow preparation of the envisioned novel anti-HCV drug candidate(s), but als o compounds for other therapeutic applications, such as antifungal and antiparasitical compounds and perhaps even derivatives that retain the excellent immunomodulatory properties of native CsA, but not the nephrotoxicity. PUBLIC HEALTH RELEVANCE: Hepatiti s C virus (HCV) constitutes a significant and rapidly growing health problem world-wide. HCV infections are associated with considerable morbitity and mortality and existing therapies allows no more than a 50% probability of eliminating the virus form an i nfected patient. The principal aim of the proposed project is to use a novel genetic engineering approach to develop new, efficacious and well-tolerated drugs for the treatment of HCV infections.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 162.98K | Year: 2004

DESCRIPTION (provided by applicant): There is an immediate need for efficient, novel antifungal drugs. The fungus Aureobasidium pullulans produces a cyclic peptide know as Aureobasidin A (AbA) which is a very potent, fungicidal drug that is currently bar

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