Playing Games with Protein-Structure Prediction
Researchers from three US universities have developed a multiplayer, online game aimed at engaging nonscientists in solving complex protein-structure prediction problems.
The game, called Foldit, features a motivation and reward structure comprising a score system, player statuses, ranks and forums. So far, over 57,000 have already contributed, encouraged by user-friendly versions of algorithms to encourage gameplay.
The team of researchers behind that game, who are based at the University of Washington (Seattle, CO, USA), Carnegie Mellon University (Pittsburgh, PA, USA), and the University of North Carolina (Chapel Hill, NC, USA), found that human 3D structural problem solving was capable of overcoming difficult prediction problems where computer algorithms could come unstuck. However, they observed that when starting from a simple linear chain of amino acids, the computer came out on top.
Speaking to Future Medicinal Chemistry, Zoran Popovi, who co-authored a recent paper describing the game, said, “Our work shows that some challenging problems in biochemistry can be solved by a game-based human-computer collaboration, even though the same problems cannot be solved by computers or people alone”.
The algorithms are based on the University of Washington’s Rosetta@home project structure methodology. Highly-ranked Foldit players excel at solving taxing structure-refinement problems in which significant backbone rearrangements are necessary to achieve the burial of hydrophobic residues. Players working collaboratively develop an array of novel strategies and algorithms and unlike computational approaches, they explore not only the conformational space, but also that of possible search strategies.
The researchers suggest that the work points to a potential new pathway for scientific discovery that could be applied to many other scientific problems – including those of a nonscientific nature – within the game framework, which maintains human interest in the problem-solving. Furthermore, added Popovi “our framework shows how complete novices can be brought to high levels of expertise (for protein structure prediction in this case), significantly increasing the collective human expertise on a particular topic of interest.”
The researchers are now developing games targeting other hard-to-solve problems, including vaccine and drug design, and the design of nanotechnology mechanisms (molecular-size machines). They are also investigating educational resources based on the game framework, such as how to develop platforms for teaching early mathematics and various science curricula.
Sources: Cooper S, Khatib F, Treuille A et al. Predicting protein structures with a multiplayer online game. Nature 466, 756–760 (2010).
Rosetta@home website http://boinc.bakerlab.org/rosetta/
New Candidate Compound Identified for Treatment of Chagas Disease
Researchers at the Federal University of São Paulo (Brazil) have reported details of a compound that could serve as an effective drug candidate against Chagas disease, the infection caused by the parasite Trypanosoma cruzi, which affects approximately 18 million people and results in up to 50,000 deaths per year in tropical regions.
Although benznidazole, which is currently used to treat Chagas disease, is effective when treating acutely infected patients, it is less so against chronic infections and results in severe side effects in elderly patients.
The team led by Alisson Matsuo identified a palladium complex, known as 7a, which acted against T. cruzi. They found it inhibited cell division and was also effective against T. cruzi, even at very low doses. In addition, it was over 300-times more toxic to parasites than mammalian cells, as well as more effective than benznidazole in all in vitro and in vivo experiments.
Speaking to Future Medicinal Chemistry, Matsuo said, “It could substitute or even be combined with Benznidazole… The main advantage of 7a is that it has quite a fast trypanocidal effect, killing the parasites in minutes as compared to benznidazole, which needs 24 h to have trypanocidal activity”. The researchers hope that the high efficacy of 7a could spur on the development of second-generation compounds directed at the same target with low production costs and decreased toxicity.
“The importance of our results is therefore to provide a proof of principle that this type of compound can be used as a drug against Chagas and that it could be very effective against other kinetoplastid-related pathogens such as Leishmania”, added Matsuo.
The researchers now plan to investigate the target of 7a in trypanosomes. “This is a key step. It certainly acts through the mitochondrion of T. cruzi, which presents significant differences when compared with the mitochnodria of mammalian cells. We are also planning to evaluate whether 7a is effective in completely clearing the parasites from infected animals at later stages of infection”. The team also intends to further investigate the pharmacokinetic properties and in vivo toxicity of compound 7a, which will could help in the design of alternative delivery methods.
Source: Matsuo et al.In vitro and in vivo trypanocidal effects of the cyclopalladated compound 7a, a drug candidate for treatment of Chagas’ disease. Antimicrob. Agents Chemother. 54(8), 3318 DOI: 10.1128/AAC.00323-10 (2010) (Epub ahead of print)..
Nanocarriers Use ‘Peek and Treat Approach’ to Fight Alzheimer’s Disease
Investigators at the University of Texas and University of Houston (TX, USA) have unveiled a novel approach for the imaging and therapy of Alzheimer’s disease. Nicknamed ‘peek and treat,’ the new technology, which employs nanocarriers to package contrast agents, can simultaneously locate amyloid-beta (Aβ) plaques and aid the therapy of an AD-afflicted brain by using the nanocarriers to transport therapeutic agents.
Alzheimer’s disease is the most common form of dementia and is characterized by the aggregation of Aβ peptide into plaques and tau fragments into neuronal tangles. In individuals suffering from the condition, which has been estimated to currently affect 30 million people worldwide, the Aβ plaques can accumulate up to 10–20 years before clinical symptoms become manifest.
These plaques can go unidentified for a number of years using conventional MRI medical imaging techniques, due to the difficulty in obtaining a sufficiently high concentration of contrast agent at the plaque location. MRI, a non-invasive imaging technique used to visualize the internal structure of the body, works using a magnetic field to align hydrogen atoms in water; in vivo. MRI scanning provides contrast between various soft tissues in the body.
Contrast agents or contrast media are compounds that enhance the visibility of structures or fluids so that they are able to be detected in medical imaging. Gadolinium, a contrast agent used in MRI scanning, works by using its seven unpaired f electrons to induce the rapid relaxation of surrounding water molecules, thereby enhancing the quality of the scanned image. In order for the amyloid plaques to be highlighted in the MRI scan, a high concentration of agent must be present at their location.
However using the peek and treat approach, because of their binding affinities to Ab plaques either side of the blood–brain barrier, nanocarriers can be used to transport a sufficient concentration of gadolinium to the amyloid plaques and deliver targeted therapeutics.
The approach has been tested in a mouse model and if approved at clinical trials, could improve the efficiency of current MRI imaging, as well as deliver an array of therapeutic compounds.
Source: Scientists explore peek-and-treat approach to Alzheimer’s disease. www.uthouston.edu/sbmi/story.htm?id=2180334
Confidence is Growing in Pharma Sector, Claims Report
An international report on economic recovery claims that over half of senior executives in the pharmaceutical industry are now more confident about their prospects than at the beginning of 2010.
The study, ‘Tools for Recovery’, which drew on polling of more than 1000 senior business figures across China, the USA, Europe and the United Arab Emirates, states that the pharmaceutical sector is “One of most optimistic areas of the global economy and has taken a proactive approach to combating the economic climate”. Furthermore, it adds that businesses in the sector “Have been most focused on increased customer relationship management (CRM) activity to aid recovery over the last 18 months.”
The report also reveals that over the coming 12 months companies are planning to invest in three key areas: changing products and services (48%), CRM activity (45%) and increasing staff reorganisations (45%).
The industry has faced a difficult 18 months, which have seen “55% of pharmaceutical businesses cutting discretionary spending, while 39% had to make redundancies.” Janet Knowles, head of the life sciences team at Eversheds, said that “While economists have signaled the official ending of the recession, there is little doubt that challenging economic conditions persist.” Yet despite these circumstances, “most pharmaceutical companies have survived and even thrived”. She added, “there are encouraging signs of a general trend towards reducing cost-cutting measures in the year ahead and a greater desire to invest and focus on growth.”
However, the report also reveals that pessimism still exists, with one in four senior executives from across all sections stating that they are less confident now than at the beginning of 2010.
The study makes the case that businesses in China and Russia “have led the charge in trying to drive demand, by searching for new market opportunities”. While China is also leading the way as regards to international expansion, just 18% of companies in the USA are investigating international opportunities.
Source: Eversheds Consulting www.eversheds.com
Stapled Peptides to Be Commercialized
Swiss pharmaceutical company Roche has recently announced investment in the novel drug technology of stapled peptides.
Stapled peptides, the creation of Harvard University researchers Gregory L Verdine, Stanley J Korsmeyer and Loren D Walensky, first came to light in the mid-1990s when Verdine and colleague Schafmeister developed a chemically-stabilized a-helical peptide that was ‘locked’ into place by a hydrocarbon staple. As a result, the stapled peptide was resistant to protease activity.
The α-helix is a common motif in the secondary structure of protein. It is a spiral conformation in which each backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier.
α-helical protein structures are common mediators of the intracellular protein–protein interactions governing biological pathways. Although they are capable of interfering with and stabilizing intracellular protein–protein interactions, native helical peptides have low potency, are unstable and inefficient transporters of substances to cells. Research conducted by Verdine et al., has however shown that these problems can be overcome by chemically modifying α-helical protein structures in a process that they call ‘hydrocarbon stapling.‘
A hydrocarbon staple is generated from (S)-α-(2‘-pentenyl)alanine peptides containing olefin-bearing tethers. These (S)-α-(2‘-pentenyl)alanine peptides are situated so that the olefinic tethers, which are reactive, are positioned on the same face of the α-helix. The resulting hydrocarbon-stapled peptides, as well as being protease-resistant as mentioned earlier, are cell-permeable and bind with increased affinities for their targets. The research has important implications for therapeutic delivery. Stapled peptides are resistant to protease activity, in contrast to unstapled peptides, which rapidly degrade peptides in vivo, reducing or eliminating altogether, their therapeutic potential.
Aileron Therapeutics (MA, USA), the company responsible for developing the stapled peptides, has recieved US$25 million from Roche to commercialize development. A commitment has been made for up to US$1.1 billion to be paid to the Massachusetts-based developer if they succeed in developing stapled peptide therapeutics for five target diseases. Although the diseases have not been named, the therapeutic areas include cancer, inflammation, metabolism-, CNS and virus-related disorders.
Source: Roche backs new method for drug delivery to cells.www.nytimes.com/2010/08/24/health/24drug.html?_r=1&ref=health