How drugs get those tongue-twisting generic names

C&EN Associate Editor Carmen Drahl explains that until 1961 there was no standard for assigning drugs generic names, which are different from brand names like Tamiflu (oseltamivir), Nexium (esomeprazole) and Herceptin (trastuzumab). That's when three medical organizations created the U.S. Adopted Names (USAN) Council to assign simplified alternatives to the unwieldy proper names the International Union of Pure & Applied Chemistry gives to molecules. For instance, under USAN's guidance, "cis-8-methyl-N-vanillyl-6-nonenamide" becomes "zucapsaicin." The council recommends generic names to an international agency of the World Health Organization. The tongue-twisting words the USAN Council creates are products of "stems" that describe a drug's characteristics, which Drahl likens to the Latin and Greek roots of many English words.

Drahl writes that these stems describe everything from a drugs' function to its shape. For instance, the "-prazole" ending of Nexium's generic name, esomeprazole, reveals that it is a type of antiulcer medication. Similar drugs will have the same stems in their names, allowing those familiar with the stems to crack the code. The USAN Council is careful to avoid words that are difficult to pronounce in foreign languages or that may have other meanings abroad. Sometimes, Drahl notes, a generic name will also include hints about its developer that a drug company has suggested to the council, as in carfilzomib, which recognizes molecular biologist Philip Whitcome and his wife Carla.

More information: Where Drug Names Come From - http://cen.acs.org … es-Come.html

Provided by American Chemical Society (news : web)

Scientists create novel RNA repair technology

The new study, published January 17, 2012 in an advance, online edition of the journal ACS Chemical Biology, describes a method to find compounds that target defective RNAs, specifically RNA that carries a structural motif known as an "expanded triplet repeat." The triplet repeat, a series of three nucleotides repeated many more times than normal in the genetic code of affected individuals, has been associated with a variety of neurological and neuromuscular disorders.

"For a long time it was thought that only the protein translated from this type of RNA was toxic," said Matthew Disney, an associate professor at Scripps Florida who led the new study. "But it has been shown recently that both the protein and the RNA are toxic. Our discovery of a small molecule that binds to RNA and shuts off its toxicity not only further demonstrates that the RNA is toxic but also opens up new avenues for therapeutic development because we have clearly demonstrated that small molecules can reverse this type of defect."

In the new research, the scientists used a query molecule called 4', 6-diamidino-2-phenylindole (DAPI) as a chemical and structural template to find similar but more active compounds to inhibit a toxic CAG triplet repeat. One of these compounds was then found effective in inhibiting the RNS toxicity of the repeat in patient-derived cells, which demonstrated an improvement in early-stage abnormalities.

"The toxic RNA defect actually sucks up other proteins that play critical roles in RNA processing, and that is what contributes to these various diseases," Disney said. "Our new compound targets the toxic RNA and inhibits protein binding, shutting off the toxicity. Since the development of drugs that target RNA is extremely challenging, these studies can open up new avenues to exploit RNA drug targets that cause a host of other RNA-mediated diseases."

Disney and his colleagues are already hard at work to extend the lab's findings.

More information: "Chemical Correction of Pre-mRNA Splicing Defects Associated with Sequestration of Muscleblind-Like 1 Protein by Expanded r(CAG)-containing Transcripts," Amit Kumar et al. http://pubs.acs.or … 21/cb200413a

Provided by The Scripps Research Institute (news : web)

New study sheds light on evolutionary origin of oxygen-based cellular respiration

As the central process by which cells capture and store the chemical energy they need to survive, cellular respiration is essential to all life on this planet. While most of us are familiar with one form of respiration, whereby oxygen is used to transform nutrients into molecules of adenosine triphosphate (ATP) for use as energy ("aerobic respiration"), many of the world's organisms breathe in a different way. At the bottom of the ocean and in other places with no oxygen, organisms get their energy instead using substances such as nitrate or sulfur to synthesize ATP, much the way organisms did many billions of years ago ("anaerobic respiration").

While less well-known, this latter type of cellular respiration is no less important, fuelling the production of most of the world's nitrous oxide (N2O), an ozone depleting and greenhouse gas 310 times more potent than carbon dioxide. As the enzyme responsible for catalyzing the reactions underlying anaerobic respiration, nitric oxide reductase (NOR) has attracted increasing attention in environmental circles. The mystery of NOR's catalyzing mechanism, however – which accounts for a staggering 70% of the planet's N2O production – remains largely unsolved.

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This is a schematic representation of the proton transfer pathways for the NO reduction reaction in cNOR and qNOR, and the proton pumping pathway in COX. The direction of the proton transfer is denoted by red dotted arrows. cNOR has a proton transfer pathway from the outside of the cell to the catalytic site for the NO reduction reaction. In sharp contrast to this, there is no proton transfer pathway from the outside of the cell in qNOR. Unexpectedly, however, we identified a proton transfer pathway from the inside of the cell to the catalytic site in qNOR. In COX, protons are pumped from the inside to the outside of the cell through the catalytic site. The location of the proton transfer pathway we identified in qNOR (pink color) is similar to a part of the proton pumping pathway in COX. Credit: RIKEN

With their latest research, the team sought an answer to this mystery in the origin of an evolutionary innovation known as the "proton pump". To accelerate ATP-synthesis, aerobic organisms harness the potential of an electrochemical concentration gradient across the cell, created by "pumping" protons out using energy from an oxygen reduction reaction. The enzyme powering this mechanism, cytochrome oxidase (COX), is genetically and structurally similar to NOR, suggesting a common ancestor. No evidence of any "pump", however, has been detected in anaerobic organisms.

That is, until now. Using radiation from the RIKEN SPring-8 facility in Harima, Japan, the world's largest synchrotron radiation facility, the researchers probed the 3D structure of qNOR and discovered a channel acting as a proton transfer pathway for a key catalytic reaction. While not itself a proton pump, the position and function of this pathway suggest it is an ancestor of the proton pump found in COX. The finding thus establishes first-ever evidence for a proton pump in anaerobic organisms, shedding light onto the mysterious mechanisms governing the production of nitrogen oxide and the evolutionary path that led to their emergence.

Provided by RIKEN (news : web)

A salt-free primordial soup?

The saltiness of our blood is often cited as evidence that life originated in the ocean. However, some researchers contend that the first chemical steps toward biology would have been easier in freshwater rather than saltwater.

The exact location for the origin of life is still a wide open question, but many scientists have assumed that it happened somewhere in the ocean.

"The main argument for a marine origin is that there is so much seawater," says David Deamer of UC Santa Cruz. Roughly 98% of the Earth's water bodies are salty, and this percentage was likely much higher 4 billion years ago when we think the first life-forms made their appearance.

But Deamer doesn't think quantity is a substitute for quality. Seawater, in his estimation, is too reactive with certain biomolecules to have served as the "broth" for the primordial soup.

A freshwater origin seems to have been what Charles Darwin was proposing when he imagined the spontaneous formation of biomolecules in "some warm little pond."

Deamer and his colleagues are testing Darwin's idea, but with the temperature turned up. They have gone to several geothermally heated "ponds" around the world to see if they can't cook up some of the more complex molecules of life in these freshwater environments. Deamer recounts these adventures in a new book called "First Life: Discovering the Connections between Stars, Cells, and How Life Began."

His critics might say the work could use a pinch of salt.

The ocean in your veins

It's no accident that our blood is about a quarter as salty as the ocean. This level is tightly regulated by the kidneys. Our cells will die if the salt level in blood and other fluids goes too high or too low.

The normal salt that we are familiar with is sodium chloride (NaCl). In solution, the salt breaks up into ions: specifically positively-charged sodium ions and negatively charged chloride ions. All cells – human and otherwise – spend a great deal of time shuffling these and other ions around. This shuffling is necessary to maintain the fluid pressure inside the cell, but it also creates electric potentials that provide a kind of "battery" for performing certain cellular functions.

"This sort of bioenergy is common to all life forms," says Shiladitya DasSarma of the University of Maryland Biotechnology Institute.

The ubiquity of ion-mediated potentials in cells may be telling us something about where life got started.

"I wouldn't think ions could play such an important role unless they were around in the beginning," he says.

DasSarma believes that the first organisms arose in salt water that was perhaps extremely salty. The early ocean was perhaps twice as salty as it is today. Moreover, the ingredients of life may have been concentrated by evaporation in a seaside pool or lagoon, which would have concentrated the salt as well.

Bursting life's bubble

The problem with seawater, according to Deamer, isn't the salt, per se. Seawater also contains other ions, like those of magnesium and calcium, which carry a charge of +2. These so-called divalent ions react unfavorably with certain building blocks of life.

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Lipid molecules will spontaneously form layers and vesicles. Credit: Henrik Skov Midtiby

For example, calcium ions readily bind with phosphate, thus making this molecule unavailable for important biological functions, such as energy transfer (in the case of adenosine triphosphate, or ATP) and genetic coding (as part of the backbone of DNA and RNA).

Deamer is especially concerned with the effect that divalent ions have on simple fatty acids. These "soapy" molecules – generically called lipids – line up together to form closed vesicles. Several scientists have theorized that self-forming "bubbles" of this sort might have served as a kind of rudimentary cell membrane for the very first organisms.

However, the simple vesicles can't form in seawater because the divalent ions react with the fatty acids. People with mineral-rich "hard" water in their homes are familiar with this chemistry. Soap products don't lather as well with hard water, which has high concentrations of calcium and magnesium ions that react with the soap molecules to form a solid that we call soap scum.

"Seawater would definitely precipitate fatty acids, preventing membrane formation," says Jack Szostak of Harvard University. "So I agree with Dave Deamer that primitive cells had to live in a fresh water environment. "

Throwing the catalyst out with the seawater

The challenge for Deamer is that those divalent ions are far from a nuisance when it comes to other aspects of biochemistry.

DasSarma points out that divalent magnesium ions are needed for important phosphate chemistry, and calcium ions play a vital role in cellular signaling.

Moreover, "some of those divalent ions are transition metals, which I think of as being involved with ligands in pre-macromolecular catalysis," says Harold Morowitz of George Mason University.

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A three-dimensional view of a model protocell approximately 100 nanometers in diameter. Credit: Janet Iwasa, Szostak Laboratory, Harvard Medical School and Massachusetts General Hospital

Transition metals are elements (like iron, manganese and nickel) that occupy the middle of the Periodic Table. They trade electrons fairly easily, which makes them good catalysts for driving chemical reactions.

When transition metals combine with small organic molecules called "ligands," they can drive important chemical reactions. Nowadays, this catalysis is done by proteins, but these large molecules are so complex that it's hard to imagine them being around at the dawn of life. Morowitz believes transition metals were necessary to get the biological ball rolling.

Michael Russell from the Jet Propulsion Lab seems to agree: "It is the inorganic elements that bring organic chemistry to life." And he goes on to stress that these elements can only stay in solution in saltwater (with its abundant chloride ions), otherwise they tend to precipitate into solids where they no longer can play their biological roles.

Contrary to Deamer's position, Russell doesn't believe life necessarily needed a lipid vesicle in the beginning. He thinks the prebiotic chemistry could have begun inside tiny pores of rocks. Here, proteins and DNA could have assembled in a closed environment.

"It's the proteins that do the work," Russell says. "The lipids are merely the castle wall."

Membranes-first

Deamer doesn't deny that some of the first biological steps may have occurred inside pores or on the surface of clay minerals. But eventually, organisms freed themselves from these fixed structures and ventured out into open water. And that's when they would need a good "container."

"At some point during its origin, life started using membranes," Deamer says.

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Ferric citrate is a structure formed from the transition metal iron and citrate, a compound produced by plants, algae, and many bacteria. Morowitz and his colleagues propose that structures like this could have catalyzed the formation of molecular building blocks, leading ultimately to the formation of complex molecules essential for the origin of life. Credit: Marine Biological Laboratory

As any fish will tell you, there are ways to make membranes that are "salt-proof," but these are complicated structures that need to be synthesized by enzymes or something similar, says Deamer. The far easier route is to use spontaneously forming membranes that work great in freshwater. Even though divalent ions would be scarce in this environment, the first proto-cells could still probably scavenge some if needed.

"I certainly would not claim that life began in distilled water," Deamer says. He believes life would need some ions to get going. "It's just that seawater is too much of a good thing."

So where might early life have found a nice freshwater launching pad? The Earth had no continents 4 billion years ago, as the planet was essentially one big ocean. But geologists believe that there were volcanic islands, like Hawaii and Iceland, which could have trapped fresh rain water in ponds or lakes.

Szostak believes these freshwater bodies could accumulate useful organic molecules (in contrast to the ocean where everything tends to get diluted). Being near volcanoes could have provided heat for creating wet-dry cycles. Experiments have shown that these cycles can concentrate lipid molecules to help them organize into membranes.

Deamer has witnessed first-hand these wet-dry cycles in ponds next to modern-day volcanoes in Kamchatka, Hawaii and California. He and his colleagues went so far as to dump lipid molecules into the ponds to see if they might form membranes "in the wild." The answer was no. The organic material attached itself to clay minerals at the bottom of the ponds (something that wouldn't have likely been a problem on the early Earth).

But these field tests haven't deterred Deamer.

"I've learned from visiting these places what to do to simulate these environments in the lab," he says.

His team has built a "hot pond" simulator. Little vials with freshwater and the basic ingredients of life are heated to above 60 degrees Celsius and routinely re-wetted with "rain water" from a syringe. Recent results have shown that membrane-forming lipids not only form vesicles, but they may help drive DNA replication -- something that modern cells need protein enzymes to do.

All the simulations have so far used freshwater, but Deamer says they plan to test saltwater to see how the results change.

The salt habit is hard to break.

Source: Astrobio.net (news : web)