TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay
Apr13

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Researchers may like to think they’re pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed. Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, “we’re picking a fight with natural selection.” “Picking a fight without Darwin is like going to the moon without Newton,” Read added. “We are in the dark ages when it comes to evolutionary management.” Read, director of Penn State University’s Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Get smart with the drugs you’ve already got. “We can’t rely on a continual supply of new drugs,” Read said. Many firms have already exited antibiotic research, he notes. “You can see that the markets aren’t good enough right now to drive innovation,” since new antibiotics are precious and used only for patients’ most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. “I’m not saying we shouldn’t discover new antimicrobials,” Read stressed. “In some situations, like malaria, it’s really critical. But we don’t want to put all our eggs in that basket.” Learn from what works. “I think magic bullets are the exception rather than the rule,” Read says. But researchers should focus on why wildly successful therapies were so. “Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it’s has failed miserably in others?” Read asked. Make the right matches for combination therapies. Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that’s left is the other drug, a monotherapy. “And that’s dangerous,” a breeding ground for resistance, Read cautions. “You want to be combining drugs that have similar half-lives.” Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony’s lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can...

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TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore
Apr12

TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Gregory Petsko knows why he came to TEDMED. “I’m looking for Al Gore,” he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn’t one to mince words. And he’s nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He’s looking for a charismatic champion to take up a biomedical cause: in Petsko’s case, it’s support for research in Alzheimer’s disease. Petsko and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer’s at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: “This is a man who hears a bomb ticking.” Alzheimer’s statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. “And yet I hear no clamor,” he said. “I hear no sense of urgency.” Petsko shared some not-yet-published work with TEDMED’s audience. His team is looking at a less-trod path of Alzheimer’s biology– the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi–the cell’s recycling center, or to the lysosome for snipping. For Alzheimer’s, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer’s (Neuron, DOI: 10.1016/j.neuron.2006.09.001).   Petsko’s team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing. It’s important for the Alzheimer’s field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley’s Haas School of Business and is part of the Rosenberg Alzheimer’s Project, a nascent organization that supports alternative avenues in Alzheimer’s research. “For a while, at least, the Alzheimer’s space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories,” he says. Even though those theories aren’t fully played out, “we still think it’s useful to start looking for other strands,”...

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Liveblogging First-Time Disclosures From #ACSSanDiego
Mar24

Liveblogging First-Time Disclosures From #ACSSanDiego

Watch this space on Sunday as I cover the public unveiling of five drug candidates’ structures. I’ll be liveblogging the “First Disclosures of Clinical Candidates” symposium at the San Diego ACS National Meeting, which runs from 2PM to 5PM Pacific. 1:30PM It’s half an hour before the start of the session and the big ballroom is still pretty empty. Expect that to change in short order. 2:30PM LX4211 Company: Lexicon Pharmaceuticals Meant to treat: type 2 diabetes Mode of action: dual inhibitor of sodium glucose transporters 1 and 2, which play key roles in glucose absorption in the gastrointestinal tract and kidney Medicinal chemistry tidbits: this drug candidate had Lexicon’s chemists refamiliarizing themselves with carbohydrate chemistry. Most inhibitors of sodium glucose transporters incorporate D-glucose in some way. Lexicon’s chemists realized they could try something different– inhibitors based on the scaffold of L-xylose, a non-natural sugar. The team has already published a J. Med. Chem paper (2009, 52, 6201–6204) explaining that strategy. LX4211 is a methyl thioglycoside-the team went with a methyl thioglycoside because upping the size too far beyond a methyl lost activity at SGLT1. Status in the pipeline: LX4211 is currently completing Phase IIb trials. 3:00PM BMS-927711 Company: Bristol-Myers Squibb Meant to treat: migraine Mode of action: antagonist of the receptor for calcitonin gene-related peptide- increased levels of this peptide have been reported in cases of migraine Medicinal chemistry tidbits: This team recently published an orally bioavailable CGRP inhibitor, BMS-846372 (ACS Med. Chem. Lett., DOI: 10.1021/ml300021s). However, BMS-846372 had limited aqueous solubility, something that might make its development challenging. To improve that solubility, the BMS team sought to add polar groups to their molecule, something that’s been tough to do with CGRP inhibitors historically. In the end, the team managed to add a primary amine to BMS-846372’s cycloheptane ring while maintaining CGRP activity, leading to BMS-927711. Status in the pipeline: Phase II clinical trials 3:05 lots of questions from the audience for this talk! One questioner notes (as was noted in talk) that 4 CGRP inhibitors had gone before this drug in the clinic, and not made it through. Speaker notes that this candidate is more potent than others at CGRP (27 picomolar). 3:53 We’re a bit behind schedule but got plenty of good chemistry… GSK2636771 Company: GlaxoSmithKline Meant to treat: tumors with loss-of-function in the tumor suppressor protein PTEN (phosphatase and tensin homolog)- 2nd most inactivated tumor suppressor after p53- cancers where this is often the case include prostate and endometrial Mode of action: inhibitor of phosphoinositide 3-kinase-beta (PI3K-beta). Several lines of evidence suggest that proliferation in certain PTEN-deficient tumor cell lines is driven primarily by PI3K-beta....

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Antibacterial Resistance – Learning Bacterial Tricks
Mar23

Antibacterial Resistance – Learning Bacterial Tricks

Virulent bacteria are growing increasingly resilient against our best antibiotics. Each day seems to bring a new story: MRSA outbreaks, resistant salmonella, or tough-to-treat tuberculosis. Just last week, World Health Organization director-general Dr. Margaret Chan delivered an address in Copenhagen, where she cautioned: “We are losing our first-line antimicrobials . . . in terms of replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare.” (Click here for The Haystack’s past coverage of the development of new antibacterials). Why have our drugs stopped working? Recent research from St. Jude’s (Science, 2012, 1110) attempted to answer that question. Using X-ray crystallography, a technique used to see structures at the atomic level, the researchers were able to capture a critical moment when a drug binds to DHPS, its bacterial enzyme target. The scientists could then predict how bacteria evolve to dodge further biocidal bullets. The antibacterial medicines caught in the act by the St. Jude’s researchers are the sulfa drugs (see right), former front-line treatments many doctors push to the bottom of treatment regimens, due to increasingly resistant bacterial strains. Researchers knew resistance had something to do with the drugs’ mechanism of action; sulfa drugs mimic the binding of PABA – para-aminobenzoic acid, a compound found in many sunscreens (Chemical Note: PABA occurs naturally as bacterial vitamin H1, and can also be found in yeast and plants. Chemists often borrow naturally-occurring compounds for industrial uses; two prominent examples are vanillin and Vitamin C). Disruption of this PABA binding shuts down bacterial DNA replication, stopping reproduction. Before now, however, no one had succeeded in growing crystals of the active site that actually showed the drugs interacting with the enzymatic intermediate. Let’s take one more step back: how does PABA attach itself? The enzyme we’re discussing, DHPS, catalyzes bond formation between PABA and intermediates known as pterins (see picture, left). Earlier researchers believed that this molecular hook-up operated by an SN2 mechanism, a reaction where the PABA kicks out a small piece of the pterin to form a new C-N bond. We chemists would say that SN2 means concerted bond formation, meaning that PABA would bind at the same time as the leaving group (OPPi), well, leaves. Turns out that picture’s not quite right: it’s more SN1-like, which means that the pterin first forms a positively-charged, enzyme-stabilized species! As you can imagine, this is no small feat, since the reaction works at physiological pH, in water, which could hydrate the intermediate (but doesn’t). Nope – instead, this charged molecule sits around waiting for a PABA – or a sulfa drug – to bind to it. When PABA binds, the complex exits...

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Exploring Rational Drug Design
Feb17

Exploring Rational Drug Design

Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets? A new review, currently out on J. Med. Chem. ASAP, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew! Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as The Curious Wavefunction and Practical Fragments will feel right at home! We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein. Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding. Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review). But these...

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Celgene & Avila Forge Permanent Ties

Today brought a spate of M&A activity in the biotech space, with Amgen unveiling a $1.2 billion bid for Micromet, and Celgene agreeing to pay up to $925 million for Avila Therapeutics. Both deals brought the acquirer a drug in development to treat blood cancers, while also adding a platform technology to their research engines. Being all about the chemistry, The Haystack is particularly interested in the Celgene/Avila deal, which involves covalent drug development technology. Celgene is paying $350 million upfront, with the promise of up to $195 million more if Avila’s lead covalent drug candidate, AVL-292, reaches the market. Pushing other covalent drugs through the pipeline could garner Avila shareholders another $380 million. So what is a covalent drug, anyway? As C&EN’s Lila Guterman described last fall, covalent drugs form a permanent link with their target. By comparison, most conventional drugs are designed to reversibly bind to their targets—in other words, they can stick and “un-stick” to a protein. The beauty of a covalent drug is that its specificity and potency means it can be given in low doses. As Guterman explains, patients only be given enough of the drug for molecule to reach each target protein molecule, and then another dose only when the body has generated more of that target protein. The low dose means less potential for drug-drug interactions and off-target effects. Indeed, for years, scientists avoided developing covalent drugs out of fear that serious toxicity will arise if a covalent drug happens to permanently stick itself to the wrong protein. Check out Guterman’s piece for a cautionary toxicity tale from none other than “Rule-of-Five” inventor (and former Pfizer researcher) Christopher Lipinski. The current generation of covalent drugs, however, is designed to assuage those fears through their highly selective and weakly reactive nature. Avila isn’t the only one banking on better molecular design leading to successful drugs: Zafgen’s obesity drug candidate ZGN433 also covalently binds to its target, an approach that—if it works—could enable it to sidestep the side effect issues that have plagued the obesity drug space. So are these covalent drugs worth the price tag? Avila’s pipeline is relatively young, meaning there isn’t a lot of data to go on: AVL-292 is in Phase I studies in lymphomas; a compound targeting mutant EGFR is also in Phase I trials; meanwhile, two Hepatitis C drug candidates in preclinical studies. The company has also made public preclinical date on its PI3Kα-selective inhibitor (the same target as Intellikine’s INK1117, one of the drivers behind Takeda’s $190 million acquisition of...

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