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Category → Academe

Shedding Light on Cancer Cells

Quyen Nguyen is a surgeon at the University of California, San Diego who has worked with chemists to develop molecular beacon type dyes that light up when they come into contact with cancerous tissue or nerve cells. This could give surgeons a sort of chemistry-based augmented reality, showing them exactly where and where not to cut.

Amides: Humble But Useful

A heartfelt thank-you to Chemjobber and See Arr Oh for helpful discussions!

CENtral Science’s benevolent overlord, Rachel Pepling, has organized a blog carnival around the theme of “your favorite chemical reaction”. For the Haystack’s contribution, I thought it would be appropriate to write about a reaction medicinal chemists might find familiar. So I re-read See Arr Oh’s post about which types of reactions were really the most common in the med-chem toolkit. I decided on amide formation, which sits just about at the top of the list. I’m not sure it’s my favorite chemical reaction; I’ve got a special place in my heart for the Heck reaction (or Mizoroki-Heck reaction), though I’ve already blogged extensively about it. But every amide bond formation I ran in grad school worked. That’s justification enough for me!

If this necklace represented a peptide or protein, amide bonds would be the little metal links. (Shutterstock)

Amides are the chemical ties that bind amino acids together to form peptides and proteins. Amides also turn up in a variety of other small molecules that nature makes. So it’s not surprising that amides are frequently found in drugs. Take a look at University of Arizona chemist Jón T. Njarðarson’s poster of top brand name drugs and marvel at the amide-y goodness.

Amide bond formation isn’t accomplished by a single, archetypical chemical reaction– far from it. I thought I’d provide a brief overview of some classic chemistry in this area and then move into a selection of modern-day additions to the amide-construction toolkit. Continue reading →

LaMattina & Breslow to Talk Future of Pharma

We wanted to point Haystack readers to an upcoming event hosted in conjunction with our parent organization, the American Chemical Society, and Société de Chemie Industrielle: On September 14, our own Rudy Baum will moderate a panel discussion between former Pfizer R&D head John LaMattina and Columbia University chemistry professor Ron Breslow. The topic? “New Business Paradigms for Pharmaceutical Companies.” If the lively discussion today on twitter over the arrival of the “niche blockbuster” (or as Chemjobber coined “nichebuster”) model for pharma is any indication, folks are pretty interested in how drug firms are going to survive in a post-blockbuster era. For those living in the NY/NJ area, you can witness what is sure to be some great banter in person; for everyone else, feel free to sign up for the webcast.

Difficult C. difficile Infections – New Drug, New Targets

Trust your gut . . . scientifically speaking.  From belly-button bacteria to classification of signature microflora (all the various microbes that populate the intestinal tract), it feels like recent popular “culture” grows best in a petri dish. Many scientists now classify humans as superorganisms, meaning our survival depends on a host of “good” internal bacteria that digest fiber, make vitamins, and help the immune system. But what happens when these good bacteria suddenly get wiped out by a non-selective antibiotic? This sets the stage for a Clostridium difficile intestinal conquest.

Simple contact transmits this bacterium between patients in hospitals, causing antibiotic-assisted diarrhea, bloating, and potential colitis. When a patient is treated with a broad-spectrum antibiotic, C. difficile survive by forming spores with tough outer coats, only to thrive again when there are few other bugs in the gut with which to compete.

Two new players have recently entered the fight against the difficult C. difficile: first, Optimer Pharmaceuticals’ new narrow-spectrum antibiotic for C. diff. treatment, Dificid (fidaxomicin), approved in May 2011. This antibiotic macrolide belongs to the tiacumicin class of natural products, members of which have been known since Abbott first isolated compounds from fermentation broths in 1987. Dificid specifically inhibits Clostridium RNA polymerase enzymes; without these enzymes, gene transcription halts, and the cells die.

Clearing the infection is great, but wouldn’t it be nice to ease the intestinal pain while the drug takes hold?

Researchers at UTMB-Galveston might have found a good target for drugs that could do just that. In the August advanced online publications at Nature Medicine, Tor C. Savidge at UTMB-Galveston reports on human metabolites that can inhibit C. difficile toxins TcdA and TcdB, the major agents behind painful antibiotic-assisted diarrhea.  S-nitroso-glutathione, a nitroso (NO)-conjugated version of glutathione found in stool samples of infected patients, can “pass off” its NO group to the sulfur of a specific cystine amino acid residue in the toxins, shutting down their activity. The authors point out that instead of active site binding, the normal mode of action for most enzyme inhibitors, this NO seems to inhibit the toxins via an allosteric site, meaning they bind somewhere else on the toxin but still impair its function. Potency for in vitro inhibition is still in the high micromolar range (43-57 µm), but the study may point the way to the development of more selective NO-transfer drugs.

Sweet Science: Glucose Regulates Stem Cells, Cancer

Most people think of glucose, a humble sugar, as the fuel for several critical body functions, including muscle contraction, brain function, and a host of cellular processes. As it turns out, glucose function might also make a prime target for the development of regenerative medicine and cancer treatments.

Researchers at the Mayo Clinic led by Dr. Andre Terzic report in Cell Metabolism that glucose plays a pivotal role in “re-induction” of pluripotent stem cells (iPSC) from cells called fibroblasts.  These rapidly dividing cells, which normally build connective tissues like collagen, can be convinced to shutter their oxidative, mitochondria-based metabolism in favor of a glycolytic pathway, essentially changing the cells to iPSCs in the process. 

Terzic et al, Cell Metabolism 2011

How does one rewire cellular metabolism?  Expose mouse fibroblasts to a nuclear reprogramming kit (which uses viruses to rewrite nuclear DNA), and then grow them in a high-glucose solution. The scientists used 1H NMR metabolic profiling to monitor changes in cellular metabolism in this sugary environment, finding that in roughly one week they exhibit the same metabolic footprint as embryonic stem cells. No word yet on small molecule drugs that can supplant this process.  
In other glycemic news, Stanford Medical School researchers, led by Dr. Amato J. Giaccia, have reported a small molecule capable of inducing “synthetic lethality” in renal cell carcinomas, a common type of kidney cancer. Treatment of cancer by chemical synthetic lethality combines small-molecule inhibition and genetic mutation to selectively kill cancer cells dependent on these pathways.  Carmen briefly covered this advance in the August 8 issue of C&EN.

Two transporters for glucose, GLUT1 and GLUT2, control how kidney cells use sugar; however, genetic mutations cause cancerous cells to favor GLUT1. STF-31, a sulfonamide which targets GLUT1, selectively shuts down glucose transport to those cancerous cells lacking functional VHL tumor suppressor genes, a common mutation in renal cell carcinomas. But tumor cells are notoriously tricky. The Stanford scientists wondered if in the absence of the GLUT1 activity, cancer cells: might simply use an alternative pathway called oxidative phosphorylation to stay alive.  They found that adding excess pyruvate (fuel for the oxidative phosphorylation engine) could not compensate for glucose starvation, and RCC cells still died. Other non-specific glucose transporter inhibitors (fasentin or phloretin, which hit GLUT1 and GLUT2 indiscriminately) killed normal kidney cells as well as cancerous cells, which confirms overexpressed GLUT1 as STF-31’s RCC target.

Remedium Technologies Gets A Grip On Severe Bleeding

Maryland is serious about nurturing startups. Drahl/C&EN

In the last year we’ve covered many up-and-coming drugs for controlling the delicate balance between clotting and bleeding. But what happens when something—an injury or a major surgical procedure—overwhelms that system?

Controlling big bleeds is big business, from the battlefield to the operating room. This Monday, at the American Chemical Society’s Middle Atlantic Regional Meeting (MARM) in College Park, Maryland, I heard from Matthew Dowling, CEO of a startup looking to make its mark in that space. The company is called Remedium Technologies, and it’s developing chemically modified versions of a natural biopolymer to make improved materials for stanching blood flow.

Remedium is one of several companies getting on its feet with help from technology incubation programs the University of Maryland. Representatives from several of those companies, including Dowling, gave talks at a MARM symposium on the science of startups. Look here for the MARM session’s program- it includes other companies in the drug and vaccine space, including Azevan Pharmaceuticals (which C&EN wrote about in 2001 when it was called Serenix), Leukosight, and SD Nanosciences.

The biochemical pathway that regulates clotting can’t support severe injuries that lead to profuse bleeding, Dowling said Monday. While several treatments exist for this kind of severe injury, where sutures might not work to close a wound, they have drawbacks that Dowling thinks Remedium’s technology can address.

The company’s material of choice is chitosan, a biopolymer that can be scavenged from waste shells of shrimp or crabs. Chitosan wound dressings are already on the market, but they become saturated with blood and quit sticking to tissue after about 30 minutes, which can lead to more bleeding. As a bioengineering graduate student at Maryland, Dowling developed an alternative chitosan modified with hydrophobic groups that help it stick to tissues longer. This modified biomolecule is the basis of Remedium’s technology. The company likens the material to Velcro because it is the sum total of weak interactions between hydrophobic groups and tissue that help the material stick around, Dowling explains. Once the wound has had time to heal, the material can be gently peeled away.  The chemical structure of Remedium’s hydrophobic groups is proprietary; Dowling used benzene n-octadecyl tails in graduate school.

The company has two products in development- a modified chitosan “sponge” and a spray-on blood clotting foam. Neither of those products is yet available for purchase. In College Park, Dowling showed a video demonstrating how the modified chitosan makes blood congeal quickly, and how the effect can be reversed by applying alpha-cyclodextrin. In a second video, the sponge is tested on a bleeding pig that’s had a major blood vessel cut open. This presentation is similar to what Dowling gave Monday.

Dowling has been running Remedium full-time since he obtained his doctorate from Maryland in 2010—the company was founded while he was still in graduate school, and several classmates are also in the company’s management. The company has an exclusive license for the chitosan technology from the university, and has four patents pending. It has also won several business competitions, including Oak Ridge National Laboratory’s (ORNL) 2010 Global Venture Challenge. Dowling says the university’s technology incubation resources are what made it possible for him to start a company while still in grad school, from providing office space in a building just off campus, to regular meetings with staffers knowledgeable about navigating the regulatory and funding process.

Finding Out Anesthetics’ Mode Of Action

When I think about how drug discovery has changed in the last 100 years, one of the first things that comes to mind is how much more target-focused the process is. Take aspirin as an example of the earlier model. Researchers didn’t confirm how aspirin worked until John Vane’s landmark 1971 paper, over 70 years since aspirin first hit the market.

Compare that to today’s world of drugmaking, where oftentimes researchers have to validate a target- show that it is connected to a disease and that modifying its activity might help treat that disease- before drug discovery can really get going. We’ve written about this process many times- see this account of the development of Lexicon drug candidate LX1031 for irritable bowel syndrome as an example.

But there’s at least one class of drugs where this target-based philosophy is in its infancy- anesthetic drugs. That’s because researchers are only beginning to understand the molecular basis of anesthesia. So it’s not clear which proteins to target or even whether you’d want a molecule that’s selective for one target.

The New York Times spoke with Harvard anesthesiologist Emery Brown last month about the neurobiology of anesthesia, and how being under actually is more like a coma than going to sleep. Other researchers are trying to understand anesthesia at the molecular level, like chemists Ivan Dmochowski and Bill Dailey, and anesthesiologist Rod Eckenhoff of the University of Pennsylvania. I visited their labs yesterday on a jaunt to Philadelphia. They’re among a small number of research teams building fluorescent or light-reactive versions of the anesthetics used in hospitals every day*, in order to figure out what proteins they interact with and which of those are relevant to inducing anesthesia. They’ve got their work cut out for them- for one thing, the anesthetics that are administered by inhalation, such as isoflurane and sevoflurane, bind to a slew of proteins. But if their efforts pay off, they say they will eventually be able to help chemists build better, safer anesthetics.

After exposure to light, azi-isoflurane reacts with proteins.ACS Chemical Neuroscience

More reading: Molecular targets underlying general anesthesia, NP Franks, Br. J. Pharmacol. 2006, 147, S72.

*by anesthesiologists like the guy I married, in the interest of full disclosure.

UCSF’s Yamamoto Talks Pharma Partnering

Yesterday brought news that Keith Yamamoto has been named vice chancellor of research at University of California, San Francisco, where the pharmacologist has long been vice dean of the School of Medicine. Coincidentally, this week’s issue includes a one-on-one with Yamamoto, who is playing an instrumental role in reshaping the model for industry and academia partnerships.

In the story, we pick Yamamoto’s brain about the genesis of several groundbreaking pacts between UCSF and big pharma companies, and, more generally, his views on how industry and universities should work together to accelerate the discovery of important new medicines. He also had some thoughts that didn’t make it into print, but seemed worth sharing, about what models might not work, as well as the kinds of innovative pacts that could be formed in the future.

The old consulting agreements with universities, which commonly involved keeping one another at arm’s length, “in my view can’t work,” Yamamoto says. “The challenge then becomes, what can displace that?” he says. “No one knows the answer to that question, but what’s clear is that we need to start looking for solutions.”

Yamamoto outlines the partnership UCSF is testing out with Pfizer (click here for details on that pact), an approach that he tells C&EN aims to “fill the valley of death with people.” While we’ve written about the benefits these kind of closer ties can have for pharma, Yamamoto discusses in the article how academic researchers could benefit from a more open and collaborative relationship with pharma, and the metrics used to gauge the success of these new partnerships.

Yamamoto also had some strong views on what academia should not be doing. Namely, he thinks universities that are trying to build drug discovery centers, in essence creating a biotech within the walls of academia, are taking the wrong tack. (see here for more on that model). Trying to establish the kind of core competencies that pharma has spent years honing, such as high throughput screening, is counterproductive, he contends. Better to focus on what academic scientists do best– elucidating the underlying mechanisms of disease and developing research tools to probe them–than try to push into drug development.

But that criticism is not just limited to universities. NIH is creating its own drug discovery engine through the proposed translational science center, a move Yamamoto also thinks is mistaken. “We need to realize that the best way to be able to move toward each other is not by deciding to do what the other side does,” he says. “It’d be much better for us to keep doing what we do well, but to do it in a more interactive and communicative way.”

The models UCSF is trying out are not the only way forward, and Yamamoto believes more innovation will be needed in order to accelerate the discovery of better, more targeted medicines. “There are some experiments to be done in the realm of pre-competitive public-private partnerships,” he says. Building consortia between academia, industry, government, and regulatory agencies could enable scientists to tackle the kinds of scientific questions “that no single institution can or should take on.” For example, developing better animal models of disease or predictive models of toxicology will likely only be accomplished with the cooperation of many players in the field.

Structures May Not Solve Everything

This week’s C&EN cover story is about how X-ray crystal structures of G-protein coupled receptors (GPCRs) help the hunt for new drugs. GPCRs are already a major target for drugs (if not the most popular drug target), but until recently, researchers knew little about the finer points of their structures.

As I mentioned in that story, those high-resolution protein pictures aren’t a panacea, and they won’t replace established drug-discovery technology so much as complement it. I didn’t have room to flesh out that idea in print, so I’m posting a few researchers’ thoughts on this area here today.

Some scientists thought that GPCR X-ray structures are so far of limited utility for discovering allosteric drugs, a class of GPCR-targeted drugs that can dial activity up or down rather than turning it on or off. Some GPCR-targeted drugs on the market already work this way, such as the HIV medication Maraviroc, and many more are in development. (As an aside, I feel as though every time I attend an ACS meeting talk about GPCRs, the room is packed).

“It’s the chicken and the egg story,” says Robert Lutjens, head of core biology at Addex Pharmaceuticals, which specializes in GPCR drug discovery. To get an X-ray structure of an allosteric molecule binding to a GPCR, which would be useful for developing virtual screens, one would first need to find just the right allosteric molecule—one that stabilizes the GPCR sufficiently to enable it to be crystallized. That’s difficult to do, so powerful biological assays are still critical for finding molecules that act at allosteric sites, Lutjens says. Continue reading →

Syntex Made It Possible, Sic Manebimus in Pace, Or Sexy Man Invents Pill: An Evening With Carl Djerassi

Djerassi (left) and Jacobs chat after the screening. Drahl/C&EN

The toughest part of blogging about a chemist like Carl Djerassi has been figuring out where among C&EN’s blogs the post fits. He’s ended up in The Haystack this time, my reasoning being “this is the inventor of the Pill, for Pete’s sake”, but I could just as easily imagine David musing about the pill’s natural product connections (Mexican yams!) at Terra Sigillata, or myself posting in Newscripts about Djerassi’s announcement on a work-in-progress: a new play called “Insufficiency” about a chemist who is denied tenure. (That’s all I know so far!)

It was pouring in DC last night as I sloshed four blocks north of ACS’s headquarters to the Carnegie Insitution for Science, to meet Djerassi and take in a screening of “Carl Djerassi- My Life”, an homage that follows Djerassi to Vienna, Stanford, and SoHo theaters. After the film, Djerassi and ACS Executive Director Madeleine Jacobs had an “Inside the Actors’ Studio”-style chat. Matt of Sciencegeist couldn’t make it for the evening, and I promised him via Twitter that I’d post if Djerassi said anything interesting. That’s when Chemjobber jumped in:

Chemjobber: @carmendrahl @sciencegeist If?

Touché, CJ. Clearly, as Matt then noted, I’d have to post WHEN Djerassi said interesting stuff, not if. So behold: choice Djerassi quotes from the evening. Continue reading →