32 DRUG DISCOVERY AND DEVELOPMENT
using previously approved oncology drugs can be more efficacious, safe and successful than traditional mono-therapies, making the need for predictive in-vivo models more apparent. By virtue of the fact that the two compounds selected for combination therapy would have been developed independently, determining the appropriate therapeutic dosing for such combinations also continues to be technically challenging. Te ability to test drug combinations in predictive models such as BioMAP can support the testing of pre-clinical strategies involving both development compounds and approved drugs.
Inside an anti-viral Te first study of interactions between a common clinical inhibitor and the HIV-1 protease enzyme has been carried out by an international team with members from the US, Britain and France using neutrons at the Institut Laue-Langevin (ILL) in Grenoble, France. It provides medical science with the first true picture of how an antiviral drug used to block virus replication actually works, and critically how its performance could be improved.
Te findings, reported in the Journal for Medicinal Chemistry, and the neutron techniques demonstrated at the ILL, will provide the basis for the design of a new generation of more
effective pharmaceuticals to address issues such as drug resistance.
HIV-1 protease is essential in the life-cycle of HIV where it breaks polypeptide chains to create proteins used for replication and producing new infectious virus particles. Its key role makes it one of the most studied enzymes in the world. For the past 20 years scientists have used highly intense x-rays to investigate the best way to target and block the protease’s role in spreading the virus.
However, this form of analysis has limitations. Te strongest bonds between the enzyme and an inhibitor are usually relatively weak hydrogen bonds, yet hydrogen atoms are virtually invisible to x-ray analysis, leaving scientists to speculate as to how this binding takes place.
To address this uncertainty, scientists from Georgia State University, Purdue University and Oak Ridge National Laboratory in the USA and Harwell Oxford in Great Britain used neutrons at the ILL to analyse this binding. Neutrons are highly sensitive to lighter elements, allowing the team to identify the positions of every hydrogen atom involved in the system for the first time, and see which were involved in bonding. Te inhibitor studied was Amprenavir (APV), first approved for clinical use in 1999,
and experiments were carried out on the LADI-III (quasi- Laue neutron diffractometer) instrument at the ILL.
Te neutron studies revealed a very different picture to that inferred from the x-ray studies which had overplayed the importance of many of the hydrogen bonds. In fact the team found only two really strong hydrogen bonds between the drug and the HIV enzyme.
While this may seem concerning, it actually presents drug designers with a set of new potential sites for the improvement of the drug’s surface chemistry to significantly strengthen the binding, thereby increasing the effectiveness of the drugs and reducing the necessary dosages. Based on their new understanding the team proposed a number of next steps to make these improvements, including: replacing weaker bonds with a greater number of stronger hydrogen bonds; and improving the strength of the existing hydrogen bonds.
Matthew Blakeley of the Institut Laue-Langevin said: “Tis study perfectly illustrates the benefits of neutrons in drug design due to their unique sensitivity to hydrogen atoms.”
Toxicity screening In another development, Eurofins Scientific has signed an agreement with GE
Warwick wins award for Chagas hunt D
omainex, a drug discovery company specialising in translational research support, has announced that the recipient of its first
Discovery STAR award is professor Vilmos Fulop of the University of Warwick. The award will give Fulop access to Domainex’s
drug discovery capabilities to support his research for a much-needed new treatment for Chagas disease - a potentially life-threatening disease. Also known as American trypanosomiasis, Chagas disease causes
www.scientistlive.com
upwards of 14,000 deaths annually. It is caused by the protozoan parasite Trypanosoma cruzi. “Domainex received many strong applications to
its Discovery STAR award scheme, but professor Fulop’s project stood out as he had all the elements needed to start a drug discovery project in this area of unmet medical need,” said Eddy Littler, ceo of Domainex.“We very much look forward to helping professor Fulop to identify inhibitors of his drug target, and hope that in doing so he will be able to access further funding that
will support our joint efforts towards finding a new cure for this terrible disease.” The company will provide Fulop with drug discovery
guidance and exclusive access to its LeadBuilder virtual hit screening technology. Following the identification of hits using this approach, Fulop, who has been working with the University of Warwick’s innovation support team Warwick Ventures, will be looking for additional funding to progress his work to identify potential new drug candidates against Chagas disease.
Healthcare for the exclusive right to offer GE Healthcare’s Cytiva Cardiomyocytes for drug discovery and early development cardio toxicity screening services.
Te agreement allows Eurofins Panlabs to provide a novel offering for an early predictive measure of cardiac toxicity and function in a cost-effective and time-efficient manner compared to current expensive and time- consuming animal testing models. Te initial range of cardiotoxicity screening services covered by the exclusive right will be expanded during the term of the agreement.
In drug development, up to three quarters of toxicity problems remain undetected until preclinical or later stages. Cardiotoxicity and hepatotoxicity are common causes of drug safety liabilities and withdrawal of drugs during development. Te availability of more biologically relevant and predictive assays and cell models is key to helping improve the success rate and reducing the cost of the drug discovery and development process.
GE Healthcare is pioneering the development of human cell-based models such as Cytiva Cardiomyocytes, which provide a biologically relevant alternative to current cell models and primary cells for predictive cardiotoxicity testing.
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92