The researchers discovered longdaysin by screening thousands of compounds with a chemical robot. (Credit: UC San Diego)
Compound With Potent Effects on the Biological Clock Discovered
PlosBiology.com, December 14, 2010 — Using an automated screening technique developed by pharmaceutical companies to find new drugs, a team of researchers from UC San Diego and three other research institutions has discovered a molecule with the most potent effects ever seen on the biological clock.
Dubbed by the scientists “longdaysin,” for its ability to dramatically slow down the biological clock, the new compound and the application of their screening method to the discovery of other clock-shifting chemicals could pave the way for a host of new drugs to treat severe sleep disorders or quickly reset the biological clocks of jet-lagged travelers who regularly travel across multiple time zones.
“Theoretically, longdaysin or a compound like it could be used to correct sleep disorders such as the genetic disorder familial advanced sleep syndrome, which is characterized by a clock that’s running too fast,” said Steve Kay, dean of UCSD’s Division of Biological Sciences, who headed the research team, which published its findings in the December 14 issue of the journal PLoS Biology. “A compound that makes the clock slow down or speed up can also be used to phase-shift the clock — in other words, to bump or reset the hands of the clock. This would help your body catch up when it is jet lagged or reset it to a normal day-night cycle when it has been thrown out of phase by shift work.”
The researchers demonstrated the dramatic effects of longdaysin by lengthening the biological clocks of larval zebra fish by more than 10 hours.
“Longdaysin is the champion by far in how much it can move the clock,” said Kay, whose laboratory at UCSD had found compounds in previous studies that could shift the biological clock by as much as several hours at most. “We were really surprised to find out how much you can slow down the biological clock with this compound and still have a clock that is running.”
Biologists in Kay’s laboratory and the nearby Genomics Institute of the Novartis Research Foundation, who were led by Tsuyoshi Hirota, the first author of the paper, discovered longdaysin by screening thousands of compounds with a chemical robot that tested the reaction of each compound with a line of human bone cancer cells that the researchers’ genetically modified so that they could visually see changes in the cells’ circadian rhythms. This was done by attaching in the cells a clock gene to a luciferase gene used by fireflies to glow at night, so that the cells glowed when the biological clock was activated. A chemical robot screened more than 120,000 potential compounds from a chemical library into individual micro-titer wells, a system used by drug companies called high-throughput screening, and automatically singled out those molecules found to have the biggest effects on the biological clock.
Once Kay’s group had isolated longdaysin, it turned to biological chemists in Peter Schultz’s laboratory at The Scripps Research Institute to characterize the molecule and figure out the mechanisms of how it lengthened the biological clock. That analysis showed that three separate protein kinases on the compound were responsible for the dramatic effect of longdaysin, one of which, CK1alpha, had previously been ignored by chronobiology researchers.
“Because this compound doesn’t just hit one target, but multiple targets, it showed us that if you want to shift the biological clock in a major way you have to hit multiple kinases,” said Kay.
The researchers then showed that longdaysin had the same effect of lengthening the biological clock in mouse tissue samples and zebra fish larvae that carried luciferase genes attached to their clock genes.
“We were really encouraged to find that when we added longdaysin to these living zebra fish, we lengthened the biological clock and didn’t see any obvious deleterious effects,” said Kay. “They grow normally while they are exposed to this compound. That showed us that our high-throughput assay works and accurately predicts how the compound works on the biological clock of a living fish. The next thing to do is to try this in a mammalian system.”
Kay’s research team plans to test longdaysin on mice in the near future, but its goal isn’t to develop longdaysin into a drug.
“Longdaysin is not as potent as we would like,” he adds. “This will be a tool for research.”
Other co-authors of the paper besides Hirota and Schultz were Warren Lewis, Eric Zhang, Ghislain Breton and David Traver of UCSD; Jae Wook Lee of TSRI; Xianzhong Liu, Michael Garcia Eric Peters of the Genomics Institute of the Novartis Research Foundation; and Pierre Etchegaray of the University of Massachusetts Medical School.
The study was funded by grants from the National Institutes of Health.
GoogleNews.com, December 14, 2010 — The world is facing a crisis: Bacteria have become more and more resistant to virtually all existing antibiotics, yet many companies are abandoning the field in favor of more lucrative medicines.
People are proposing various solutions, such as offering financial incentives to the pharmaceutical industry to spur the development of vitally needed antibiotics. But along with creating new drugs, we can get more life from our existing antibiotics and maintain their utility. As the head of a company focused on the development of compounds to treat and prevent a wide range of infections without causing bacterial resistance, this is an issue I find both fascinating and vitally important. In my opinion, there are five ways we can extend the functional life of our antibiotic arsenal.
1. Do the obvious
In a recent New York Times article, Ramanan Laxminarayan, director of the Extending the Cure project on antibiotic resistance at the policy organization Resources for the Future, suggested that the government should focus on conserving the effectiveness of existing antibiotics by preventing their unnecessary use in people and farm animals, and by requiring better infection control measures in hospitals.
These are crucial steps, which should be taken immediately. First, we must stop and assess the use of antibiotics as additives to the feed of our farm animals, and specifically prevent the unnecessary use of antibiotics in animals that are not sick. The U.S. Congress has already urged farmers to stop the overuse of antibiotics in animals because it is creating new, drug-resistant strains of bacteria that can spread to humans. A recent CBS news report spotlighted microbiologist Stuart Levy at Tufts University, the individual who identified tetracycline resistance in chickens more than 30 years ago. In his research, nearly all of the E. coli in the intestinal tracts of the chickens become tetracycline-resistant after one week of treatment.
2. Assess the impact
Sub-lethal quantities of antibiotics are known to create an environment for the development of resistance and multi-drug resistance mechanisms. We need to monitor the fate of all the mega-quantities of antibiotics sold as prescriptions and as over-the-counter medicine: Do they end up in our wastewater systems and landfills and become a breeding ground for new superbugs? What happens to the groundwater runoff from farms, sewage systems, and landfills?
3. Explore entirely different drugs
We must look for antibiotics utilizing new mechanisms without the development of resistance. Simply adding new drugs to existing classes isn’t cutting it. My company is developing a new class of agents with a novel mechanism of action that kills pathogens without the potential for resistance. These are fast acting, broad-spectrum, multi-targeting agents that do not persist in the environment.
Confirmatory experiments in our labs are slated for publication in 2011. The preliminary experiments indicate that our Aganocide compounds exert their activity against pathogens by the rapid and preferential inactivation of specific amino acid residues on essential membrane proteins, such as ATP machinery or ion channels which are located on the membrane of the bacteria. However, this machinery is protected inside of the mammalian cells. The consequence of this inactivation induces a change in the protein’s tertiary structures and results in dysfunction, dysregulation or protein shedding from the membranes of pathogens. The end result is a fast-acting, broad-spectrum antimicrobial agent that is safe to mammalian cells within a therapeutics window. We continue to confirm these findings and integrate these observations into the elucidation of the mechanism of action as we develop this new class of antimicrobial agents.
4. Inactivate multiple essential targets
When we attack bacteria with agents targeted against one particular cellular mechanism — for example, fluoroquinolones target DNA gyrase — the bugs simply select for a mutation to that mechanism that make them resistant, and the agent becomes ineffective. This will always be true of targeted agents, so we wind up with more of these agents every few years. We urgently need a parallel initiative in the development of multi-target agents, such as non-antibiotic agents that can inactivate essential protein targets that mutations cannot sidestep, and are not damaging to human tissues. As stated above, our company is currently pursuing multi-target agents.
Subtle and selective multi-target agents to which bacteria cannot develop mutational resistance are the key to solving this huge problem. They are pivotal for our survival and should have fast-track consideration by all agencies.
5. Encourage and incentivize the industry
Finally, we should encourage and incentivize the pharmaceutical and biotech industry to develop safe and effective non-antibiotic anti-infectives that could replace all topical antibiotics for eyes, skin, ear, over-the-counter antibiotics, etc.
Overall, we need to understand the sources of antibiotic resistance — whether it originates in farms, sewers, landfills, or other locations — and find ways to save our precious few antibiotics for systemic blood-borne infections. Otherwise, the overall result will be fewer effective drugs to treat bad bugs.
Ron Najafi, PhD is chairman and CEO of NovaBay Pharmaceuticals, Inc (NBY)., an Emeryville, California-based biotechnology company developing anti-infective compounds for the treatment and prevention of antibiotic-resistant infections. Ron Najafi can be reached at email@example.com.
Ron Najafi, PhD, Chief Executive Officer and Chairman of Emeryville, CA-based NovaBay Pharmaceuticals (AMEX & TSX: NBY, http://www.novabaypharma.com), a clinical stage biopharmaceutical company developing products for the treatment or prevention of a wide range of bacterial, fungal, and viral infections, was chosen as one of the “PharmaVOICE 100,” most influential leaders. “PharmaVOICE 100” is an annual list of individuals who are having a remarkable influence on the life sciences industry.
Dr. Najafi’s selection was based on his vision of developing and commercializing safe and effective non-antibiotic anti-infectives to reduce and replace usage of antibiotics in a number of non-systemic applications. He is seeking to change the paradigm of antibiotic usage. In an environment where many bacteria are becoming increasingly more resistant to antibiotics and are creating superinfections and unnecessary deaths, Dr. Najafi believes an alternative is imperative. “Dr. Najafi is impatient to reach his goal, so he impresses upon his team the need to find ways of moving things forward faster while being fully cognizant of the need to put safety first,” writes the editor of PharmaVOICE magazine. “If anyone has the will to make this goal a reality it is Dr. Najafi. A tenacious leader, ‘no’ means ‘not now’; he just doesn’t give up easily. His can-do attitude and belief that success is based on not giving up are contagious,” continued the editor.
Dr. Najafi and his team have discovered and are developing a class of non-antibiotic anti-infective compounds to treat a wide-range of infections, which they have named Aganocide(R) compounds. These compounds are based on the naturally occurring small molecules generated by neutrophils (white blood cells). According to PharmaVOICE, if all goes according to plan, the products NovBay brings to market will have a significant impact in the fight against antibiotic resistant infections including MRSA.
“Being recognized by my peers and PharmaVOICE as someone who is inspiring others and contributing to the overall improvement and advancement of our industry is a great honor,” commented Dr. Najafi. “I am most excited about this recognition of the success we have had at NovaBay, and is a direct reflection on the outstanding group of people we have that are dedicated to providing a solution to the growing problem of antibiotic resistance.”
This year’s distinguished list of one hundred leaders was selected by PharmaVOICE’s readers who nominated individuals in the industry that had inspired them; thousands of readers submitted nominations. Ultimately, the PharmaVOICE 100 was selected based on the number of nominations received and other factors, such as community and philanthropic activities.
PharmaVOICE divided the honorees into different categories that best capture their individual skill sets and expertise. Dr. Najafi was appropriately positioned in “Leaders” category. As defined by PharmaVOICE, these entrepreneurs are redefining the life-sciences industry through innovative approaches to improving technologies, processes, services, and ultimately patient care.
The PharmaVOICE article can be seen on www.pharmavoice.com/100 or you can request a copy of the article by e-mailing Janet Vasquez at firstname.lastname@example.org.
About NovaBay Pharmaceuticals, Inc.
NovaBay Pharmaceuticals, Inc. is a clinical stage biopharmaceutical company focused on developing innovative product candidates targeting the treatment or prevention of a wide range of infections in hospital and non-hospital environments. NovaBay has discovered and is developing a class of non-antibiotic anti-infective compounds, which it has named Aganocide compounds, which are based upon small molecules that are generated by white blood cells that defend the body against invading pathogens. NovaBay believes that Aganocide compounds could form a platform on which to create a variety of products to address differing needs in the treatment and prevention of bacterial and viral infections, including resistant bacteria such as MRSA. NovaBay has entered into a licensing and research collaboration agreement with an affiliate of Alcon, Inc. for use of the Aganocide compounds in the eye, ear and sinus, and in contact lens solutions. The company also has a license agreement with an affiliate of Kinetic Concepts, Inc. for the use of NovaBay’s NeutroPhase product in wound care applications.
NovaBay(TM), Aganocide(R), AgaNase(TM), and NeutroPhase(TM) are trademarks of NovaBay Pharmaceuticals, Inc. All other trademarks and trade names are the property of their respective owners.
This release contains forward-looking statements, which are based upon management’s current expectations, assumptions, estimates, projections and beliefs. These statements include, but are not limited to, statements regarding the development and potential benefits of, and the market opportunities for, NovaBay’s product candidates. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results or achievements to be materially different and adverse from those expressed in or implied by the forward-looking statements. Factors that might cause or contribute to such differences include, but are not limited to, risks and uncertainties relating to difficulties or delays in discovery, development, testing, regulatory approval, production and marketing of the company’s product candidates, unexpected adverse side effects or inadequate therapeutic efficacy of the product candidates, the uncertainty of patent protection for the company’s intellectual property or trade secrets, the company’s ability to obtain additional financing as necessary and unanticipated research and development and other costs. The forward-looking statements in this release speak only as of this date, and NovaBay disclaims any intent or obligation to revise or update publicly any forward-looking statement except as required by law.