Kim H.-J.,Westheimer Institute for Science and Technology |
Ricardo A.,Ra Pharmaceuticals |
Illangkoon H.I.,University of Florida |
Kim M.J.,Westheimer Institute for Science and Technology |
And 3 more authors.
Journal of the American Chemical Society | Year: 2011
One present obstacle to the "RNA-first" model for the origin of life is an inability to generate reasonable "hands off" scenarios for the formation of carbohydrates under conditions where they might have survived for reasonable times once formed. Such scenarios would be especially compelling if they deliver pent(ul)oses, five-carbon sugars found in terran genetics, and exclude other carbohydrates (e.g., aldotetroses) that may also be able to function in genetic systems. Here, we provide detailed chemical analyses of carbohydrate premetabolism, showing how borate, molybdate, and calcium minerals guide the formation of tetroses (C4H8O4), heptoses (C7H14O7), and pentoses (C 5H10O5), including the ribose found in RNA, in "hands off" experiments, starting with formaldehyde and glycolaldehyde. These results show that pent(ul)oses would almost certainly have formed as stable borate complexes on the surface of an early Earth beneath a humid CO2 atmosphere suffering electrical discharge. While aldotetroses form extremely stable complexes with borate, they are not accessible by pathways plausible under the most likely early Earth scenarios. The stabilization by borate is not, however, absolute. Over longer times, material is expected to have passed from borate-bound pent(ul)oses to a branched heptulose, which is susceptible to Cannizzaro reduction to give dead end products. We show how this fate might be avoided using molybdate-catalyzed rearrangement of a branched pentose that is central to borate-moderated cycles that fix carbon from formaldehyde. Our emerging understanding of the nature of the early Earth, including the presence of hydrated rocks undergoing subduction to form felsic magmas in the early Hadean eon, may have made borate and molydate species available to prebiotic chemistry, despite the overall "reduced" state of the planet. © 2011 American Chemical Society. Source
Glenn W.S.,John Innes Center |
Glenn W.S.,Massachusetts Institute of Technology |
Nims E.,Massachusetts Institute of Technology |
Nims E.,Ra Pharmaceuticals |
And 2 more authors.
Journal of the American Chemical Society | Year: 2011
Installing halogens onto natural products can generate compounds with novel or improved properties. Notably, enzymatic halogenation is now possible as a result of the discovery of several classes of halogenases; however, applications are limited because of the narrow substrate specificity of these enzymes. Here we demonstrate that the flavin-dependent halogenase RebH can be engineered to install chlorine preferentially onto tryptamine rather than the native substrate tryptophan. Tryptamine is a direct precursor to many alkaloid natural products, including approximately 3000 monoterpene indole alkaloids. To validate the function of this engineered enzyme in vivo, we transformed the tryptamine-specific RebH mutant (Y455W) into the alkaloid-producing plant Madagascar periwinkle (Catharanthus roseus) and observed the de novo production of the halogenated alkaloid 12-chloro-19,20-dihydroakuammicine. While wild-type (WT) RebH has been integrated into periwinkle metabolism previously, the resulting tissue cultures accumulated substantial levels of 7-chlorotryptophan. Tryptophan decarboxylase, the enzyme that converts tryptophan to tryptamine, accepts 7-chlorotryptophan at only 3% of the efficiency of the native substrate tryptophan, thereby creating a bottleneck. The RebH Y455W mutant circumvents this bottleneck by installing chlorine onto tryptamine, a downstream substrate. In comparison with cultures harboring RebH and WT RebF, tissue cultures containing mutant RebH Y455W and RebF also accumulate microgram per gram fresh-weight quantities of 12-chloro-19,20-dihydroakuammicine but, in contrast, do not accumulate 7-chlorotryptophan, demonstrating the selectivity and potential utility of this mutant in metabolic engineering applications. © 2011 American Chemical Society. Source
News Article | July 24, 2015
Ra Pharmaceuticals, a Cambridge, MA-based developer of peptide chemistry platform to deliver drugs with specificity of antibodies coupled with the pharmacological properties of small molecules, completed a $58.5m Series B financing. The round was co-led by RA Capital Management, Novo Ventures, and Lightstone Ventures, with participation from new investors Rock Springs Capital and Limulus Venture Partners and existing investors New Enterprise Associates (NEA), Novartis Venture Fund, Morgenthaler Ventures, and Amgen Ventures. The company intends to use the funds to generate human proof of concept data for its lead molecule, RA101495, in multiple indications, and to advance multiple product candidates derived from its proprietary Extreme Diversity™ platform, including the development of a broader pipeline of products targeting additional diseases of the complement system. RA101495 is a complement C5 inhibitor and is expected to enter Phase 1 clinical studies for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in late 2015. Led by Doug Treco, PhD, Founder and CEO, Ra Pharma develops a proprietary platform that combines in vitro display technology, a defined translation system and a variety of non-natural amino acids to produce novel drug-like peptides. Its proprietary peptide chemistry platform delivers drugs with the diversity and specificity of antibodies, coupled with the pharmacological properties of small molecules. The company’s primary clinical focus is on diseases of complement dysregulation and orphan indications defined by validated biomarkers. The company also announced today that its multi-target collaboration that was established in April 2013 with a subsidiary of Merck & Co., Inc., known as MSD outside the United States and Canada, has been extended.
News Article | July 9, 2015
DUBLIN--(BUSINESS WIRE)--Research and Markets (http://www.researchandmarkets.com/research/n9ngzz/hereditary) has announced the addition of the "Hereditary Angioedema (HAE) - Pipeline Review, H1 2015" report to their offering. This report provides comprehensive information on the therapeutic development for Hereditary Angioedema (HAE), complete with comparative analysis at various stages, therapeutics assessment by drug target, mechanism of action (MoA), route of administration (RoA) and molecule type, along with latest updates, and featured news and press releases. It also reviews key players involved in the therapeutic development for Hereditary Angioedema (HAE) and special features on late-stage and discontinued projects. The report enhances decision making capabilities and help to create effective counter strategies to gain competitive advantage. It strengthens R&D pipelines by identifying new targets and MOAs to produce first-in-class and best-in-class products.
News Article | July 23, 2015
Ra Pharma Gets $58.5M in Crossover Cash to Target Rare Blood Disease Ra Pharmaceuticals, a Cambridge,MA-based company that signed a large collaboration deal with Merck two years ago, has received a $58.5 million Series B financing to take its first drug, a potential treatment for an ultra-rare blood disorder, called paroxysmal nocturnal hemoglobinuria, into human clinical testing. PNH occurs when a part of the immune system called the complement system misfires, unleashing an attack that destroys red blood cells and causes a host of severe health problems, like blood clots and organ failure. Ra’s proposed treatment is meant to fend off the wayward immune attack. Ra’s treatment, known as RA101495, is only in preclinical testing so far—it’s got much to prove, and it’ll start down that path when its first trials begin later this year. But Ra’s goal is to someday have a drug that can compete with the likes of Alexion Pharmaceuticals (NASDAQ: ALXN), which received FDA approval in 2007 to treat PNH with its monoclonal antibody, eculizumab (Soliris), and now has a market capitalization approaching $50 billion. Ra says RA101495 is a synthetic molecule that’s like a peptide, which is a string of amino acids similar to proteins, but smaller and typically more fragile. Ra’s molecule has a modified chemical structure that enhances its stability and potency, as Xconomy has previously reported. Currently, RA101495 is injected just like most biologic drugs. Ra says its candidates have the potential to be taken orally because they still resemble a small molecule drug, however, which may help it compete with eculizumab down the line. Synthetic molecule should have a lower cost of goods than biologics, which will allow Ra flexibility in pricing and will increase patient access to therapies, Doug Treco, co-founder, president and CEO of Ra, wrote in an e-mail. Ra is developing other drugs out of these peptide-like molecules, using a platform it calls Extreme Diversity. The platform’s potential lured Merck, which cut a $200 million collaboration deal with Ra in April 2013. That agreement has been extended, the companies say. Other companies are developing peptide-based drugs that can be swallowed like pills instead of injected. Protagonist Therapeutics received a $40 million funding round last week to help test the company’s oral peptide treatment for irritable bowel disease—and conditions that rise from it—in humans. Chiasma is a Newton, MA-based biopharma company trying to develop an oral octapeptide to treat orphan diseases typically treated with injectables. It raised $101.8 million in an initial public offering last week. The Series B funding for Ra, meanwhile, will help pay for the development of RA101495 and some other drug candidates. The round includes a number of so-called “crossover” investors that typically back public companies, indicating Ra is at least positioning itself for an IPO down the road. The funding was led by RA Capital Management, Novo Ventures, and Lightstone Ventures. New investors Rock Springs Capital and Limulus Venture Partners, and existing investors New Enterprise Associates, Novartis Venture Fund, Morgenthaler Ventures, and Amgen Ventures also participated. These crossover rounds have become commonplace in biotech as money has flooded back into the sector. Another Cambridge biotech, RaNA Therapeutics, just announced a $55 million crossover round earlier this morning.