The Center for Pharmaceutical Research and Innovation (CPRI) is a University of Kentucky-based research center established by the University of Kentucky College of Pharmacy in 2012 to facilitate academic translational research and drug discovery/drug development. The UK CPRI specializes in natural product-based drug discovery from microbes found within unique environments including underground and surface coal mines, acid mine drainage and mine reclamation sites, thermal vents associated with underground coal mine fires (see coal seam fire) [1] [2] [3] [4] [5] [6] [7] [8] and deep-well drilling for carbon sequestration. CPRI also provides core support for medicinal chemistry, assay development and screening, rational drug design, computational chemistry, and ADMET. The Center collaborates with investigators focused on drug discovery or development research in the areas of cancer, drug and alcohol addiction, cardiovascular disease, infectious disease, regenerative medicine and neurodegenerative disease.
The University of Kentucky (UK) is a public co-educational university in Lexington, Kentucky. Founded in 1865 by John Bryan Bowman as the Agricultural and Mechanical College of Kentucky, the university is one of the state's two land-grant universities, the largest college or university in the state, with 30,720 students as of Fall 2015, and the highest ranked research university in the state according to U.S. News and World Report.
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration for an investigational new drug to initiate clinical trials on humans, and may include the step of obtaining regulatory approval with a new drug application to market the drug.
Acid mine drainage, acid and metalliferous drainage (AMD), or acid rock drainage (ARD) is the outflow of acidic water from metal mines or coal mines.
A coal-seam fire is a natural burning of an outcrop or underground coal seam. Most coal-seam fires exhibit smoldering combustion, particularly underground coal-seam fires, because of limited atmospheric oxygen availability. Coal-seam fire instances on Earth date back several million years. Due to fine thermal insulation and the avoidance of rain/snow extinguishment by the crust, underground coal-seam fires are the most persistent fires on Earth and can burn for thousands of years, like Burning Mountain in Australia. Coal-seam fires can be ignited by self-heating of low-temperature oxidation, lightning, wildfires and even arson. Coal-seam fires have been slowly shaping the lithosphere and changing atmosphere, but this pace has become fast and extensive at modern times, triggered by enormous mining activities.
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high GC content. Found predominantly in soil and decaying vegetation, most streptomycetes produce spores, and are noted for their distinct "earthy" odor that results from production of a volatile metabolite, geosmin.
A natural product is a chemical compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.
The calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, with calicheamicin γ1 being the most notable. It was isolated originally in the mid-1980s from the chalky soil, or "calichi pits", located in Kerrville, Texas. The sample was collected by a scientist working for Lederle Labs. It is extremely toxic to all cells and, in 2000, a CD33 antigen-targeted immunoconjugate N-acetyl dimethyl hydrazide calicheamicin was developed and marketed as targeted therapy against the non-solid tumor cancer acute myeloid leukemia (AML). A second calicheamicin-linked monoclonal antibody, inotuzumab ozogamicin an anti-CD22-directed antibody-drug conjugate, was approved by the U.S. Food and Drug Administration on August 17, 2017, for use in the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Calicheamicin γ1 and the related enediyne esperamicin are the two of the most potent antitumor agents known.
Herbimycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 and alters its function. Hsp90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the F2RL1 gene. PAR2 modulates inflammatory responses, obesity, metabolism, and acts as a sensor for proteolytic enzymes generated during infection.
Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.
Metabotropic glutamate receptor 3 is a protein that in humans is encoded by the GRM3 gene.
Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.
Translation initiation factor eIF-2B subunit epsilon is a protein that in humans is encoded by the EIF2B5 gene.
Interleukin enhancer-binding factor 2 is a protein that in humans is encoded by the ILF2 gene.
Krueppel-like factor 11 is a protein that in humans is encoded by the KLF11 gene.
NLR family CARD domain-containing protein 4 is a protein that in humans is encoded by the NLRC4 gene.
Indolocarbazoles (ICZs) are a class of compounds that are under current study due to their potential as anti-cancer drugs and the prospective number of derivatives and uses found from the basic backbone alone. First isolated in 1977, a wide range of structures and derivatives have been found or developed throughout the world. Due to the extensive number of structures available, this review will focus on the more important groups here while covering their occurrence, biological activity, biosynthesis, and laboratory synthesis.
Glycorandomization, is a drug discovery and drug development technology platform to enable the rapid diversification of bioactive small molecules, drug leads and/or approved drugs through the attachment of sugars. Initially developed as a facile method to manipulate carbohydrate substitutions of naturally occurring glycosides to afford the corresponding differentially glycosylated natural product libraries, glycorandomization applications have expanded to include both small molecules and even macromolecules (proteins). Also referred to as 'glycodiversification', glycorandomization has led to the discovery of new glycoside analogs which display improvements in potency, selectivity and/or ADMET as compared to the parent molecule.
ABT-724 is a drug which acts as a dopamine agonist, and is selective for the D4 subtype. It was developed as a possible drug for the treatment of erectile dysfunction, although poor oral bioavailability means alternative drugs such as ABT-670 may be more likely to be developed commercially. Nonetheless, it continues to be used in scientific research into the function of the D4 receptor.
A nanonet is a net with fibers on the scale of nanometers. The net can be composed of carbon, metals, silicon, or peptides, such as nanonets composed of the defensin HD6. The word nanonet is also used in reference to a nanoscale communication network, which also uses key components on the scale of a hundred nanometers as officially defined in IEEE P1906.1.
Venturicidins are a group of antifungal compounds. The first member of this class was isolated from Streptomyces bacteria in 1961. Additional members of this class were subsequently isolated and characterized. An antifungal substance "aabomycin A" was isolated from Streptomyces in 1969. However, in 1990 it was reported that aabomycin A is actually a 3:1 mixture of two related components, which were then named aabomycin A1 and aabomycin A2. The structures of these were shown to be identical with those of the previously characterized compounds venturicidin A and venturicidin B, respectively. A new analog, venturicidin C, was recently reported from a Streptomyces isolated from thermal vents associated with the Ruth Mullins coal fire in Kentucky.
Brevianamide F , also known as cyclo-(L-Trp-L-Pro), belongs to a class of naturally occurring 2,5-diketopiperazines. It is the simplest member and the biosynthetic precursor of a large family of biologically active prenylated tryptophan-proline 2,5-diketopiperazines that are produced by the fungi A.fumigates and Aspergillus sp. It has been isolated from the bacterium Streptomyces sp. strain TN58 and shown to possess activity against two Gram-positive bacteria, S.aureus and Micrococcus luteus, and has also been isolated from Bacillus cereus associated with the entomopathogenic nematode, Rhabditis (Oscheius) sp. and shown to have antifungal activity against T. rubrum, C. neoformans and C. albicans, better than amphotericin B. Although the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food, cyclo(L-Trp-L-Pro) has only been found as a minor 2,5-diketopiperazine (8.2ppm) in autolyzed yeast extract. Initially cyclo(L-Trp-L-Pro) and its DL, LD, and DD isomers showed potential for use in the treatment of cardiovascular dysfunction, however they were later shown to be hepatoxic.
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