The key objective of this project involves the exploration of US rare and endangered plants and their unique host-microbiome community. These communities will be studied for their biosynthesis and production of new classes of natural products (NPs) HCV drug leads with unique MOAs. The project involves a well established collaborative relationship with the laboratories of Prof Mark Hamann and at the University of Mississippi and Tony Whitaker with RFS Pharma and Raymond Schinazi at Emory University/Atlanta VA. The collective expertise provides a unique opportunity to explore new sources for treatments for HCV which are resistant to current forms of treatment.
The specific aims of this program include: 1. A collection and phylogenetic analysis of 100 endangered plant associated bacteria and fungi strains each year. Phylogenetically diverse and unique US endangered plant species (20) will be evaluated for bacteria and fungi which inhibit HCV. This will provide 500 unique bacteria and fungi over the course of the five year project period. 2. Innovative epigenetic tools will be applied to stimulate production of secondary metabolites from silent genes. These will include regulatory tools available commercially as well as those derived from the host endangered plant itself. Each new strain will be subjected to 10 or more epigenetic tools. Highly sensitive HPLC with UV-TOF-ELS detection and small volume NMR will be utilized to evaluate NP production from genes silent under standard culture conditions. 3. A unique HCV real time PCR assay is featured in this grant application as a primary screen to identify extracts obtained from Aim 2 with HCV selectivity for fractionation in aim 4. 4. Active leads from Aim 3 will be purified using HPLC with MS, UV and ELSD detection. Repeated bioassays using real time PCR will be completed until HCV selective metabolites are generated. Natural product structures will be assigned using integrated NMR, HPLC-MS, UV, IR and X-ray crystallographic analysis.
The proposed study is highly relevant to public health and addresses the need for new and better treatments for HCV. Unique natural products from rare/endangered US plants and their associated microbial community will be explored for the potential to control HCV which remains resistant to existing treatments. Hundreds of unusual and rare microbes will be studied using a variety of epigenetic tools to stimulate metabolite expression from silent genes. Pure HCV selective natural products will be evaluated carefully for MOA and activity against drug resistant isolates.
|Oh, Joonseok; Liu, Haining; Park, Hyun Bong et al. (2016) In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes. Biochim Biophys Acta :|
|Zhang, Yiguan; Valeriote, Frederick; Swartz, Kenneth et al. (2015) HPLC Plasma Assay of a Novel Anti-MRSA Compound, Kaempferol-3-O-Alpha-L-(2",3"-di-p-coumaroyl)rhamnoside, from Sycamore Leaves. Nat Prod Commun 10:1383-6|
|Hwang, In Hyun; Oh, Joonseok; Zhou, Wei et al. (2015) Cytotoxic activity of rearranged drimane meroterpenoids against colon cancer cells via down-regulation of Î²-catenin expression. J Nat Prod 78:453-61|
|Gogineni, Vedanjali; Schinazi, Raymond F; Hamann, Mark T (2015) Role of Marine Natural Products in the Genesis of Antiviral Agents. Chem Rev 115:9655-706|
|Waters, Amanda L; Oh, Joonseok; Place, Allen R et al. (2015) Stereochemical Studies of the Karlotoxin Class Using NMR Spectroscopy and DP4 Chemical-Shift Analysis: Insights into their Mechanism of Action. Angew Chem Int Ed Engl 54:15705-10|
|Hoye, Thomas R; Alarif, Walied M; Basaif, Salim S et al. (2015) New cytotoxic cyclic peroxide acids from Plakortis sp. marine sponge. ARKIVOC 2015:164-175|
|Wang, Bin; Waters, Amanda L; Valeriote, Frederick A et al. (2015) An efficient and cost-effective approach to kahalalide F N-terminal modifications using a nuisance algal bloom of Bryopsis pennata. Biochim Biophys Acta 1850:1849-54|
|Chatwichien, Jaruwan; Basu, Subhasree; Murphy, Maureen E et al. (2015) Design, Synthesis and Biological Evaluation of Î²-Carboline Dimers Based on the Structure of Neokauluamine. Tetrahedron Lett 56:3515-3517|
|Schrader, Kevin K; Hamann, Mark T; McChesney, James D et al. (2015) Antibacterial Activities of Metabolites from Platanus occidentalis (American sycamore) against Fish Pathogenic Bacteria. J Aquac Res Dev 6:|
|Waters, Amanda L; Peraud, Olivier; Kasanah, Noer et al. (2014) An analysis of the sponge Acanthostrongylophora igens' microbiome yields an actinomycete that produces the natural product manzamine A. Front Mar Sci 1:|
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