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Excellus BlueCross Blue Shield has joined a national effort to lower the cost of some overpriced generic drugs. Excellus, 17 other local Blue Cross companies and the Blue Cross Blue Shield Association have partnered with nonprofit generic drug maker Civica to start making new outpatient generic drugs through a new Civica subsidiary. The first new generics should be available by early The subsidiary is putting together its list of the first medicines it will produce, Chitre said. The drugs will be available to everyone, whether they are Blue Cross members or not — including government payers such as Medicaid, she said. Hospitals across the country have routinely faced shortages of critical medicines. Other initiatives are working on new generic drugs for hospitals, too, including ProvideGx, a program of Premier Inc. Over the years, the increased use of generic drugs over brand names has saved a lot of money for health plans and their members, who face smaller co-pays. For every 1 percent increase in generic use, Excellus was able to cut premiums by 2 percent, Chitre said. Of the generic drugs approved between and , less than two-thirds of them were actually launched, she said. But four is the number of competitors needed to drive down prices and improve affordability, she said. So the new Civica subsidiary will get permission to manufacture some key generic drugs — either making them directly or through contracts with other manufacturers. The Blue Cross plans are putting up some of the capital to pay for the subsidiary. Some of the first drugs chosen for manufacturing are for multiple sclerosis, cancer and ulcerative colitis, she said. Right now, the Mohawk Valley Health System is monitoring 50 drugs that are in short supply, Carucci said. The health system was always able to use it in every newborn, but only after calling the manufacturer and getting an emergency supply as a birthing center, she said. Carucci said she remembers a drug costing pennies for a hundred pills when she began her pharmacy career 36 years ago. Now it costs hundreds of dollars, she said. Without competition, prices for drugs used in hospitals have spiked, too. And prices frequently go up sharply right after a shortage, she said. Civica now has 18 drugs that are either available or in-production. Although those generics only go to its member health systems, the initiative helps everyone, Carucci said. ProvideGx, in which the health system participates, was established in January with plans to target 60 crucial drugs. And Premier Inc. Each participating hospital will be obligated to buy 65 percent of the volume it needs of each ProvideGx drug from the program, Carucci said. Excellus program aims to make generic drugs more affordable. Staff Writer Times Herald-Record. Facebook Twitter Email.

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Official websites use. Share sensitive information only on official, secure websites. Correspondence: johnstm iu. All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins HSP60 — also known as GroEL in bacteria. While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness caused by Trypanosoma brucei parasites and drug-resistant bacterial infections in particular Methicillin-resistant Staphylococcus aureus — MRSA. Intriguingly, during our studies we found that three known antibiotics — suramin, closantel, and rafoxanide — were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3, approved drugs, natural products, and known bioactives identified hit inhibitors of the Escherichia coli GroEL chaperonin system 4. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition. Molecular chaperones are a class of proteins that cells have developed to help fold polypeptides to their native states, or target them for degradation. While some organisms contain more than one HSP60 or GroEL isoform, one has always proven to be essential, at least in the micro-organisms thus far evaluated. To further support that this interaction was real, in the present study, we analyzed the suramin-GroEL binding properties using Isothermal Titration Calorimetry see the Supporting Information for a detailed protocol for this experiment. An isotherm for a representative suramin-GroEL binding analysis is presented in Figure 2 , with the thermodynamic parameters, binding affinities, and binding stoichiometries averaged from triplicate analyses presented in Table 1. Future studies will need to explore this, but are beyond the scope of the present study. Structures of compounds previously found to inhibit E. Representative analysis of the binding of suramin 28 to E. The lower panel shows the integrated data solid squares fit to a single-site binding model solid line. The molar ratio refers to the binding stoichiometry of suramin to monomeric GroEL. Binding parameter results are averaged from three replicate analyses. Binding is predominantly entropically driven, with a moderate enthalpic contribution to affinity. In three additional follow up studies to our high-throughput screen, we explored the antibacterial properties of a subset of 22 of our hit GroEL inhibitors, plus additional compound B analogs and a series of analogs based on a bisarylamide hit-to-lead scaffold. In this study, we screened against the Library of Pharmaceutically Active Compounds LOPAC and the MicroSource Spectrum libraries, which together contain 3, approved drugs, natural products, and known bioactive molecules. A schematic representation of this multiplexed assay is presented in Figure 3 , with a detailed description of the protocol provided in the Supporting Information. Since MDH and Rho have orthogonal enzymatic reactions i. MDH catalyzes the oxidation of NADH in the presence of mesoxilic acid, while Rho catalyzes the conversion of cyanide to thiocyanate — two very different enzymatic reactions , we have typically found that these two refolding assays are effective at removing false-positive compounds that inhibit the refolded reporter enzymes. Percent inhibition results for these two assays are presented in Table S2 in the Supporting Information. While this suggests that if we tested the libraries at higher concentrations, or relaxed our inhibition cutoffs, we may find even more hits, we refrained from doing so as we had already obtained a high hit rate of 4. In this assay, a solution containing GroES and a binary complex of denatured malate dehydrogenase dMDH bound to GroEL was dispensed into the wells of a well microplate. In this coupled assay, the extent of chaperonin inhibition is proportional to the amount of enzymatic activity, and thus refolded MDH, present. In the same plate, we then added the malachite green phosphate reporter reagents to evaluate chaperonin-mediated hydrolysis of ATP. Upon examination of the hits, we found a wide range of molecular structures, from as small as the single aryl mesalamine 23 to large, macrocyclic natural products like thiostrepton 24 and ivermectin While singleton hits were identified, several hits were found that fell into distinct scaffold clusters, including analogs of suramin 1 , 22 , 28 , chalcones 35 , 43 , 44 , ivermectin 31—33 , agaric acid 7 , 8 , 11 , 20 , 25 , 27 , 39 , 42 , and porphyrins 5 , 19 , To further verify that hits were not false-positives owing to potential abnormalities in the library parent stocks or compounds that inhibit both the native MDH and Rho reporter enzymes, we selected a set of 60 hits to purchase purified powders of for confirmatory screening in our wider panel of established chaperonin-mediated biochemical assays. The structures of these hits are presented in Figure S1 in the Supporting Information , which were selected to maintain structural diversity while still probing some of the scaffold clusters. Please refer to the Supporting Information for detailed protocols of these assays, and Table 2 for a compilation of IC 50 values obtained in these assays. Consistent with results from the primary high-throughput screen, none of the compounds showed appreciable inhibition of GroEL-mediated ATPase activity. Compilation of IC 50 values from the respective biochemical assays. Compounds are ordered from most selective in the refolding assays at the top, to lower selectivity going down the table. While the green and yellow series are less selective, each still have moderate correlations between their IC 50 values obtained in the two refolding assays, with Spearman correlation coefficients of 0. Correlation plots of IC 50 values for compounds tested in the respective biochemical assays. Each data point represents results for individual compounds tested in the respective assays, with color coding of points corresponding to the selectivity classifications of compound results presented in Table 2. As indicated in panel A , For the purposes of categorizing inhibitor potencies in the various biochemical assays, we consider compounds with IC 50 values plotted in the grey zones to be inactive i. As an extension on potential selectivity concerns, because human HSP60 shares high homology to bacterial E. As seen in Figure 4C , there is a high correlation for compounds inhibiting both E. These high correlations were not surprising based on results we have reported for other inhibitors, where we have only found a few scaffolds that can selectively inhibit E. For chaperonin inhibitors that do affect the viability of human cells, whether they are natural products, synthetically derived, or even approved drugs or not, it will be important for future studies to determine whether or not their cytotoxicities are HSPdependent. As a first-pass indicator of general cellular toxicity, we employ Alamar Blue-based cell viability assays with a small panel of human cell lines from different tissues. To further inform on the possibility that some of these compounds may exhibit promiscuous and pan-assay interference effects, we searched the PubChem database to see how many assays each of these compounds has been screened in, and the number of assays in which they have been classified as active hits. While some hits have only been reported tested in a handful of assays, most have been tested in hundreds, or even thousands, of assays. To more easily assimilate the data, in Figure S2A and S2B , we binned the aggregate results of the percentage assays that each molecule was reported active hits in, compared to their total number of reported assays. For example, We exercise a word of caution in over-interpreting these results, though, as we have not further dissected the actual assays that each compound was tested in — for example, it would actually be beneficial if compounds were tested and reported active in a high proportion of infectious organism proliferation assays. With some compounds being tested in hundreds to thousands of assays, such a detailed analysis would be best suited for future studies of individual compounds. As an overview, we have compiled a brief listing of reported bioactivities for each of the hits in Table S1 in the Supporting Information. While the bioactivities presented are far from exhaustive, they begin to paint a picture that targeting chaperonin systems could play a significant role in a number of indications, including inflammation, autoimmunity, cancer, and, in the context of the present study, antibiotic applications. For some of these compounds, like suramin, definitive mechanisms of action have yet to be elucidated. From our two high-throughput screens, we obtained an unusually high hit rate of 4. With such a high hit and re-confirmation rate, this study suggests that targeting chaperonin systems might be a more common occurrence than we previously appreciated. These findings further incentivize broader screening of additional known drugs, clinical candidates, and natural product libraries and extracts to identify more compounds that may be functioning against chaperonin systems. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The human HSP60 expression plasmid lacking the 26 amino acid N -terminal mitochondrial signal peptide was generously donated by Dr. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Bioorg Med Chem Lett. Published in final edited form as: Bioorg Med Chem Lett. Find articles by Mckayla Stevens. Find articles by Sanofar Abdeen. Find articles by Nilshad Salim. Find articles by Anne-Marie Ray. Find articles by Alex Washburn. Find articles by Siddhi Chitre. Mabel St. Find articles by Jared Sivinski. Find articles by Yangshin Park. Find articles by Quyen Q Hoang. Find articles by Eli Chapman. Find articles by Steven M Johnson. Issue date May 1. PMC Copyright notice. The publisher's version of this article is available at Bioorg Med Chem Lett. Open in a new tab. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Evans blue. Protoporphyrin IX. Ethacrynic acid. Agaric acid. Cetylpyridinium chloride. Epigallocatechin gallate EGCG. Hexadecyltrimethylammonium bromide. Aurintricarboxylic acid. Erythrosin B. Tannic acid. Chlorophyllin sodium copper salt. L-Ascorbyl palmitate. Pontamine sky blue. Retinoic acid. Morin hydrate. Arachidonic acid. Abamectin Avermectin b1a. Crystal violet. 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