34 minute read
Appointments
Northern Lipids Inc. announces the appointment of Dr. Norbert Maurer as director of R&D. Dr. Maurer brings to NLI over 20 years of experience in the development of delivery technologies for conventional chemotherapeutic agents and biopharmaceuticals such as therapeutic antibodies and nucleic acid-based drugs. Most recently as head of formulations at CDRD, Dr. Maurer focused on the formulation of drugs, from novel small molecule therapeutics to the new macromolecular therapeutics coming from proteomics and genomics research. Previously, he was involved with a number of Vancouver-based pharmaceutical companies that tended to focus on delivery platforms. Dr. Maurer obtained his PhD in Physical Chemistry while living in Austria followed by post-doctoral training in the Biochemistry Department (The Liposome Research Unit) of the University of British Columbia. He has authored 27 peer-reviewed papers, review articles and book chapters and is named on six patents/patent applications.
Sirona Biochem Corp. has added Dr. Martin Gleave to its board of directors. Dr. Gleave is a clinicianscientist and urologic surgeon and holds numerous leadership positions in research and academia. He is currently a distinguished professor and vice chair of the department of urologic sciences at UBC and director at the Vancouver Prostate Centre (VPC). His major research focus involves the study of cellular and molecular mechanisms mediating progression of prostate cancer to its lethal stage of androgen independence, and use of this information to develop integrated multimodality therapies that specifi cally target these mechanisms. Dr. Gleave established a role for clusterin as a cancer-related cell survival protein involved in treatment resistance and developed an inhibitor, designated OGX011, which improved effi cacy of hormone- and chemo-therapies in prostate and other cancer models. He is also the scientifi c founder of OncoGenex Pharmaceuticals Inc.
Advertisement
The TVN Network has elected Russell Williams, president, Canada’s Research-Based Pharmaceutical Companies (Rx&D), as its new chair of its board of directors. Mr. Williams assumed the role at the board’s fi rst meeting held in Toronto on January 22, 2015. TVN is a not-for-profi t research network aimed at improving the care of seriously ill elderly patients, and supporting their families and caregivers. Prior to joining Rx&D, he successfully represented the Montréal riding of Nelligan for 15 years as a Liberal MNA in the National Assembly of Québec, and is well known for his advocacy for individual rights and government services focused on the needs of citizens. He continues active volunteer involvement in palliative care and, in January 2014, received the Quality End-of-Life Care Coalition of Canada (QELCCC) second annual Award of Excellence in Advocacy for his tireless advocacy for hospice palliative care. He is also well known for his championship of Canadian health research, and this commitment was honoured in November of 2014 when he received the inaugural Research Canada Leadership Award.
Aptose Biosciences Inc. has added oncology industry veteran and venture investor Dr. Erich M. Platzer to its board of directors. He brings considerable product development, clinical trial management, licensing and commercialization expertise from his career in the pharmaceutical industry. He also has a rich background in oncology and hematology from both the clinical and business perspectives. Dr. Platzer is a board certifi ed physician in internal medicine, hematology and medical oncology. Previously, Dr. Platzer was business director of oncology, global strategic marketing and therapeutic area head of oncology at Roche, Basel, where he also served as medical director in oncology and global development project leader.
BriaCell Therapeutics Corp has engaged Dr. Steven J. O’Day as principal investigator for its upcoming BriaVax™ vaccine clinical trial. Dr. O’Day is a highly specialized oncologist with a history of leading successful clinical trials, having been educated and trained at Johns Hopkins, Harvard, and Oxford. Dr. O’Day has acted as the principal investigator on over 100 clinical trials including several large, international Phase 3 clinical trials. He served as the principal investigator in BristolMyers Squibb’s Phase 3 clinical trial for its Yervoy, which included 676 patients, and saw a signifi cant improvement in overall survival for late-stage melanoma patients.
Lynne Bulger will be joining Cipher Pharmaceuticals Inc. in the role of vice president, medical and clinical affairs where she will lead the company’s clinical development and medical affairs efforts for current and new pipeline products. Ms. Bulger has 27 years of experience in drug development in the pharmaceutical industry, conducting clinical research and providing strategic medical marketing support in dermatology, rheumatology, osteoporosis and CNS. Most recently, she held the position of director medical affairs at Stiefel, a GSK company. In this role, she was responsible for medical affairs activities for Stiefel Global and Canada for 35 dermatology products. Previous to that, she was director medical and regulatory affairs at Barrier Therapeutics and director medical affairs at Hoffman-La Roche. She also served as president of the Canadian Dermatology Industry Association from 2005 to 2008. In addition to this appointment, Cipher promoted Peter Weiler to the position of vice president, business development and Linda Angaritis to the position of vice president, global regulatory compliance and quality.
The Public Health Agency of Canada announces the appointment of Dr. Matthew Gilmour as its new scientifi c director general
Russell Williams
National Public Health Laboratories, responsible for the National Microbiology Laboratory (NML) in Winnipeg, MB and the Laboratory for Foodborne Zoonoses (LFZ) in Guelph, ON. Dr. Gilmour is currently a clinical microbiologist with diagnostic services of Manitoba and an assistant professor in the department of medical microbiology at the University of Manitoba.
He is also a past employee of the Agency where he held the positions of director of bacteriology and enteric diseases and the chief of enteric diseases at the NML. As scientifi c director general, he will be responsible for managing the delivery of laboratory public health and emergency preparedness programs, providing strategic scientifi c advice to senior offi cials and representing Canada’s top human health laboratories nationally and internationally. The position is being fi lled following the retirement of Dr. Frank Plummer.
Xite Bio welcomes Bob Reekie to its team. Reekie was named the company’s new business and product manager. He will be based out of Regina, SK. Reekie has a long history of excellence in sales, marketing, and business development with Bayer CropScience (BCS), and most recently as a BCS consultant. His roles at Bayer CropScience have included director of cereal crops marketing Canada, director of marketing Western Canada, director of InterAg, and cereal portfolio manager.
Dr. Matthew Gilmour
by ePPendorf aG feature
Tips, Tricks and Information for the ergonomic design of your laboratory
The advantages of an orderly work situation are obvious. It allows one to keep all required instruments in view reduction of waste can be achieved. Thus, Kaizen implies small but nevertheless steady improvements. According to Kaizen, there are workspace should from then on be kept clean and organized (Seiso). In order to put these points into practice, a personal desire for cleanliness complete elimination of stocks; on the contrary, the availability of a certain minimum stock is a prerequisite for efficient work. A simple solution must and within reach, therefore generating smooth work flow. Instruments and devices do not have to be found and brought to the bench first. Even leaning forward and stretching the upper body in order to reach something violates the ergonomic concept of an orderly workplace. The more chaotic and untidy a workspace, the more unnecessary or even harmful additional movements are required. Finally, an untidy work area can lead to increased mental strain, since constant searching interferes with the concentration required for the actual task at hand.
One solution for lack of order stems from the principles of Kaizen (from the Japanese: “change for the better”) which is often employed in production. This Japanese term stands for a stepwise approach, with the help of which increasingly higher standards in the improvement of quality and seven forms of waste which are to be kept to a minimum: overproduction, waiting times, preventable transports, complex and useless processes, large stock, superfluous movements, as well as mistakes and useless fixes. These forms of waste are universal. They can be identified equally well in a global pharmaceutical or biotech company, in the molecular lab at a University, or in a private home. In order to reduce these forms of waste, Kaizen offers four different sets of rules: Best Point – workplace design, One Piece Flow (flow principle), 5 S-rule and Poka Yoke. The 5 S-rule prescribes five simple rules which are to be followed: first, those things which are useless and superfluous are removed from the workplace (Seiri). Those items which are then part of the work area are organized (Seiton). The thus defined and order needs to be developed and cultivated (Seiketsu). Finally, standards must be defined and implemented for these five rules to become habit (Shitsuke). The rules of Seiton and Seiso imply that means and ways must be found to organize items and, furthermore, maintain that order long term. To this end, deviations should be noticed quickly and rectified immediately and in an uncomplicated fashion. No strictly defined rules apply, as each workplace and each laboratory have their own expectations with respect to order. As such, individual creativity is essential. For example, a diagonal line drawn across the front of a row of binders in sequence will help keep these binders in the correct order. It is easy to spot missing binders immediately. In order to guarantee efficiency in the workplace/laboratory it is further necessary to avoid large stocks of gloves, tips, etc. (Seiri and Seiton). Large stocks are one of the seven types of waste which are to be avoided. However, this does not imply the be found for keeping the necessary stock without over stocking or under stocking. One such solution could be the traffic light system, where the colors green, yellow and red, in that order, represent a decreasing minimum stock. Shelves, drawers, etc. are easily and economically equipped with such a system. Most laboratories, however, present an entirely different picture: drawers are filled to the maximum with boxes of gloves, tips, etc., in a disorganized fashion. This, however, is a false assumption. It would be much better to note the threat of low supply of various items in drawers, cupboards and shelves via their “traffic lights” and to prevent this occurrence with one trip. When organizing a core workstation (Seiton) with consideration for physical-ergonomic requirements, in addition to the 5-S rules, the Best Point Principle should be consulted
feature
as well. This principle of workplace design states that items which are a part of a core work space should be kept in locations which are easiest to reach by the user. Ideally, all items would be within arm’s reach. Even in a simple office, this would be difficult to implement, and it sounds like utopia when considering the work space at hand – the laboratory. Therefore, in order to be able to implement the Best Point Principle in the laboratory, it is crucial to sort items into three different areas of reach, according to their frequency of use. The optimum area of reach is equivalent to a radius of the length of a person’s lower arm, including the hand, without stretching. This radius is the actual work area. For a range of body heights between 1500 and 1900 mm (4’11” to 6’3”), this radius is approximately 35 cm (13 ¾”). However, the maximum physiological reach comprises a radius of the length of the outstretched arm without severe leaning forward of the upper body (approx. 50 cm or 19 ½” for body heights between 1500 and 1900 mm or 4’11” to 6’3”). This is the ideal area in which items for daily use should be kept. The anatomical area of reach for persons of heights between 1500 and 1900 mm (or 4’11” to 6’3”) is up to 60 cm (23 ½”) and thus requires leaning forward in order to reach items located within this radius.
It is suitable for items used in the long term. It is recommended that one get up in order to retrieve or use them, rather than leaning over to reach. Leaning forward should generally be avoided. Within the entire work area, both hands should be used. This supports coordination and distributes strain between two hands.
Following the successful sorting of items, the ergonomic requirements during sitting and standing need to be considered. This is a part of orientation along the Best Point Principle. Mainly the task and the furniture in the laboratory determine whether one is sitting or standing while working. In fact, a German study of laboratory personnel revealed that approximately half the people sit while pipetting while the other half stands.1 If one stands exclusively, a chair with a high seat should be used as a sitting-standing support, and ergonomic workplace mats should be used. If one sits without exception, care should be taken to adjust the chair to the individual body height. The height is to be adjusted to allow the knees to form a 90 degree angle and the lower back to lean against a back rest. To the disadvantage of lab personnel, laboratory benches are often equipped with countless under-desk cupboards which preclude sitting altogether, or allow it only at an angle. From an ergonomic perspective, a combination of standing, walking and sitting is superior, as in this case all stabilizing muscles are in turn activated and relaxed, depending on the state of activity. Hence, it makes sense that following a pipetting task which has been performed while standing one would move to an office area, sit down at a table and record the data into the lab book. This combines ergonomics with responsible laboratory work.
In addition, the introduction of organization is subject to cognitiveergonomic requirements. These are extensively considered within the Poka Yoke rules of Kaizen. Poka Yoke desires to uncover mistakes in all possible areas of work as early as possible, thus helping prevent them. This is rooted in a form of process visualization, which allows one to recognize the flow and therefore “missteps.” Error reduction saves cost, energy and time. Productivity increases. Inevitably, products of higher quality are produced.
With regard to the laboratory work space, colour coding of pipettes and tips takes center stage. While many manufacturers are now colour-coding their tips, not all of these color codes actually help prevent errors. Colour codes only make sense if they are visible unequivocally from all work positions. The advantage of intelligent color coding is rooted in minimizing pipetting errors and unnecessary actions, which result from searching for the correct pipette. Apart from colour coding, there exist many other aides in the sense of Poka Yoke. A calibration warning device installed in some electronic pipettes acts as an automatic reminder for calibrations due. Some pipettes are equipped with special mechanisms which protect the volume setting from being changed accidentally. Some electronic dispensers automatically recognize the volume of the tip fitted.
The requirement for order in accordance with the rules of Seiri and Seiton extend beyond the individual workplace and are applied to the structure of the laboratory as a whole. The flow of movement in a laboratory may be compared, in a simplified view, to those in a kitchen. In 1922, the American Christine Fredericks conducted a study to analyze the organization of kitchens. To this end, she pinpointed the paths she took in her kitchen during the preparation of an evening meal with the help of a thread. The result was a chaotic structure. Based on this observation, she re-organized all utensils and appliances according to the flow during cooking and repeated the experiment. The result was considerable reduction of distance covered and faster preparation of the evening meal. Employing similar studies of the optimization of flow in the kitchen, the German architect Margarete Schütte-Lihotzky designed the “Frankfurt kitchen” in the 1920s. Parallels to the laboratory abound. Apart from over stock, many drawers and shelves contain items (single pieces, etc), the designation of which may be difficult even for a long term member of the laboratory team. Furthermore, products (e.g. samples) are often distributed among several refrigerators. The location of instruments often does not represent the work flow.
It is generally advisable to keep products and instruments which are always used together in close proximity to one another. The same is true for the storage of parts and items which are functionally related. Samples which are to be measured or processed together should be stored in the same refrigerator. A waterbath/ thermomixer should be in the vicinity of a photometer if enzyme activity is to be analyzed. As a positive side effect, the risk of contamination will be reduced. Furthermore, if possible, all work stations within a laboratory are to be organized. This will not only reduce the need for detours, but it also improves safety (toxic substances no longer need to be transported between individual laboratories, etc.). However, his type of laboratory restructuring does not aim to eliminate walking altogether.
Walking should always be a part of the daily routine in the laboratory, as it provides natural breaks from repetitive tasks, and it relaxes the stabilizing muscles. The organization described above can only be maintained over time if a long-term desire for order is created (Seiketsu). Therefore, the introduction of a new ergonomic organizational system requires the participation of all employees involved.2 Despite the participation-based approach, the realization just how effective a new organizational system can be does not appear by itself. In the beginning phase of the new organization, this realization needs to be supported by the implementation of standards and rules (Shitsuke). During the early phase, clear delegation of responsibilities for the maintenance and reinstatement of order is essential. The introduction of a schedule for order and cleanliness is helpful. However, the guarantee of cleanliness is subject to large variation according to the understanding and expectations of the individual. Thus, checklists are still required, which need to be adhered to by the person in charge according to the schedule. For example, this person makes a trip to the storage room as soon as he or she notices the need during regular check of the traffic light system. Further, the location of all individual items must be available to everyone (location of instruments, devices, consumables, chemicals, etc.).
Attitude is the readiness to react to certain environmental stimuli in either a consistently positive or a consistently negative manner. In this case, the affective component plays a major role. It represents the emotional evaluation of an object. In the case where the object to be evaluated is a task or the work in its entirety, the affective component is strongly influenced by the environment. Mainly light, noise and climate play critical roles. Especially during precision tasks such as pipetting, light which is too dim places a strain on the eye muscle (focusing). Therefore, illumination between 500 and 1000 Lux is recommended for office areas and 750 to 1500 Lux for older employees.3 The higher the demand for precision during the performance of a task, the stronger the illumination required.3 When working with electronic instruments (e.g. electronic pipettes), the illumination of the display should be adjusted to ambient light conditions. A screen which is too bright irritates the eyes in dark or dimmed rooms. As a rule, natural daylight is the best and most healthy illumination. With its unique spectrum, it regulates many physiological processes; it is a well-known fact that the circadian rhythms of humans and animals are dependent on daylight. Therefore, a laboratory should have a sufficient number of windows.
Furthermore, these windows need to be equipped with blinds against direct sunshine. Nevertheless, artificial light may be necessary from time to time, depending on the time
of year and time of day. In addition, rooms without daylight are consciously chosen for certain research projects and the experiments involved therein. Loud background noise interferes with concentration. If one is subjected to it long term, it may, in extreme cases, lead to cardiovascular disease.4 For these reasons, the noise level should be kept as low as possible in order to facilitate stress-free and concentrated work. The noise level can be expressed in decibels. The decibel is a relative value, where an increase in 10 decibels is felt to be twice as loud. Normal breathing has a noise intensity of 10 decibels, whispering is already 20 decibels, and speaking in a low voice is 40 decibels.
Hence, quiet speech is perceived to be eight times louder than normal breathing. The stress or tolerance level, respectively, is at 60 decibels and is equivalent to loud speech. During highly concentrated work, an average daily noise level of 35 to 40 decibels should not be exceeded.3 For tasks which require less concentration, 55 decibels are not to be exceeded.3
In terms of climate, a temperature between 21 and 22 °C (but not higher than 26 °C), relative humidity of 40 to 60 per cent and air current of 0.1 to 0.15 m/s (at 21 °C) are considered optimal.3 Furthermore, air should be free of toxic gases and low in carbon dioxide. Chemical aerosols and dust are also to be avoided. In order to achieve this, opening of windows for 10 minutes every day is recommended.3
feature
To see this story online visit
http://www. laboratoryfocus. ca/?p=2857
Quality Products... Guaranteed
References
1. Bruder R, Richter M,
Müller J, Heppener A, 2006: [Development of a basic ergonomic concept for different types of pipettes, internal report to
Eppendorf AG, Darmstadt: Institute for Labor
Science] [German] Entwicklung eines ergonomischen Grundkonzeptes für unterschiedliche Varianten von Pipetten, Interner Bericht an die Eppendorf AG, Darmstadt:
Institut für Arbeitswissenschaft. 2. Duell, W., 1983: [Participation-based work design. Conditions of successful intervention] [German] Partizipative
Arbeitsgestaltung. Bedingungen erfolgreicher Intervention. Psychosozial 20:71-90 3. Wittig-Goetz U, 2011: http://www.ergoonline. de/site.aspxurl=html/arbeitsplatz/arbeitsumgebung_beleuchtung/ laerm.htm http://www.ergoonline.
de/site.aspxurl=html/arbeitsplatz/arbeitsumgebung_beleuchtung/beleuchtung.htm http://www.ergo-online. de/site.aspxurl=html/arbeitsplatz/arbeitsumgebung_beleuchtung/klima_im_buero.htm 4. [Government agency for workplace protection and workplace medicine, 2003: Labor science research #124: Monitor work – noise reduction in multi-user offi ces] [German] Bundesanstalt für Arbeitsschutz und Arbeitsmedizin, 2003: Arbeitswissenschaftliche Erkenntnisse Nr. 124: Bildschirmarbeit – Lärmminderung in Mehrpersonenbüros.
Quality Products for Your Lab at Affordable Prices!
Our lab products have taken part in side-by-side comparative tests at Universities, Pharmaceutical, Government and Research Institutions around the globe. Wyvern products were found to be as good as, or better than, the name brands and were considered a higher value due to their low cost.
Our Filtration Products are Designed, Manufactured and Certified in Accordance with ISO 9001
1-888-883-3636 www.mandel.ca
feature
by mark Peterson and steven klein
Exploiting Macrocycle Space
for Drug Discovery
In the never-ending search for new pharmaceutical agents, signifi cant attention has been focused on the advances enabled by the “omics” technologies, such as genomics, proteomics and metabolomics. These innovations have led to the identifi cation and characterization of an increasing number of promising pathways and targets for therapeutic intervention.
Associated with this resurgence of novel targets, a dramatic shift in drug discovery approaches to biomolecular entities has contributed to a greater number of antibody and protein drug products appearing and advancing in the pipelines of pharmaceutical and biotech companies. Unfortunately, the chemical strategies employed to attempt to modulate these pathways and targets have not experienced a similar transformation. Indeed, many of the targets being investigated are proving intractable to the traditional small molecule structures that dominate historical corporate compound collections.
To address this dilemma, one area that has attracted considerable interest over the last few years is that of macrocycles.1,2 Macrocycles are chemical structures containing one or more rings of at least 12 atoms and, as such, are typically larg-
Target Classes
ProteinProtein Interactions
Protein-DNA Interactions
Phosphatases
Proteases
Ion Channels
Nuclear Receptors
Kinases
GPCRs
Small Molecule Drugs (MW <500) Macrocycles
(MW 500-2000) BiomolecularDrugs
Antibodies Proteins
Peptides
Antisense RNAi
FEATURE
Figure 2 Cyclenium CMRT macrocycles adopt diverse topologies
er than the 500 Da molecular weight limit imposed to traditional small molecules by the well-known Lipinski “rules of fi ve.” Importantly, this compound class effectively fi lls the gap between conventional small molecules and biomolecules (Figure 1), and can offer attractive features of each, the high potency and selectivity of biomolecules combined with favorable pharmacokinetic properties, including oral bioavailability, as well as the ease and lower cost of development of small molecules. Further, a wide assortment of natural products are macrocyclic in nature and have already proven to be a fruitful source of interesting bioactivity with a number of marketed drugs arising from this class.
Detrimentally, preparation of analogues of natural products to modulate the properties or circumvent unfavorable aspects of the initial compounds is usually not possible due to their limited quantity, signifi cant complexity, and poor synthetic accessibility. Nonetheless, macrocyclic compounds represent a potential wellspring for novel pharmacological activity and offer a number of attractive features: • Dense, complex functionality • Conformational rigidity • Structural preorganization • Display of diverse interacting groups in extended regions of three-dimensional space • Viable approach to protein-protein interaction (PPI) modulators and other diffi cult targets • Underexplored intellectual property space
To date, however, diffi culties in the de novo synthesis of macrocyclic structures, particularly in the library format required for the high throughput screening (HTS) campaigns that are a common starting point for most modern drug discovery efforts, have hampered their exploration.
Recently, this situation has changed and an array of innovative technologies have been developed that provide access to macrocyclic compounds of varying size and composition.3 These approaches range from purely chemical in nature to hybrid strategies that combine biological methods such as phage or mRNA display and directed translation systems with one or more chemical steps.4,5 The latter in particular can generate very large numbers of compounds, but tend to also be in the higher MW range, bringing concerns regarding their ability to possess drug-like properties. In contrast, pure chemical strategies often provide structures on the lower MW side of the macrocycle continuum with their concomitant higher potential for favorable physicochemical and pharmacokinetic profi les.
Intending to exploit the advantages provided by this region of macrocycle space, a research collaboration between Cyclenium Pharma, a Québec-based pharmaceutical company specializing in the discovery and development of novel drug candidates based on proprietary macrocyclic chemistry, and the Institute for Research in Immunology and Cancer — Commercialization of Research (IRICoR) along with Université de Montréal and its Institute for Research in Immunology and Cancer (IRIC) was announced in January. This collaboration will utilize Cyclenium’s proprietary QUEST Library™ of next generation macrocyclic molecules and associated hit-to-clinical candidate optimization expertise in concert with IRIC’s state-of the-art capabilities in biological target identifi cation, characterization and screening, as well as medicinal chemistry. The objective of the collaborators is to discover and develop new pharmaceutical agents for the treatment of cancer and immunological disorders.
“As a chemistry-focused company, it is critical for Cyclenium to fi nd appropriate partners, such as IRICoR, with complementary biological and pharmacological expertise, to provide a robust engine for generating new pharmaceutical agents,” commented Dr. Helmut Thomas, president & CEO of Cyclenium Pharma. “The combination of our unique CMRT™ Technology, together with the signifi cant biology, pharmacology and medicinal chemistry expertise of IRIC provides strong synergy for the development of novel therapeutics against cutting-edge targets in oncology and immunology.”
In a similar vein, Cyclenium established a collaboration with Southern Research Institute (Birmingham, Alabama, USA) in April 2014 and has indicated that additional such partnerships in their therapeutic focus areas of oncology, infectious diseases and infl ammation/pain will be announced in early 2015.
Although Cyclenium is a relatively young organization, its founders originate from one of the pioneers in the macrocycle fi eld, Tranzyme Pharma, which shuttered its Sherbrooke R&D facility in November 2013 following the merger of its parent company with Ocera Therapeutics. The Cyclenium team has capitalized on its over 15 years’ experience with a signifi cant knowledge base regarding macrocyclic drug discovery in creating its proprietary CMRT (pronounced “smart”) Technology that addresses the defi ciencies of the initial efforts in this area, which often fail to deliver compounds with properties appropriate for further development as pharmaceuticals. Indeed, the focus for Cyclenium on the lower end of macrocycle space (MW < 800) is due to the better pharmacokinetic and physicochemical profi les that can be attained with such structures. More specifi cally, CMRT macrocycles combine variable linker components with bifunctional building blocks, many derived from amino acids, to permit simultaneous investigation of a diverse chemical and topological space (Figure 2). The QUEST Library contains a representative sampling of the compounds occupying this space and enables a rapid survey of it for novel bioactivity. Once initial hits are attained, the modular construction of Cyclenium’s macrocycles simplifi es and accelerates hit-to-lead-to-clinic optimization through systematic variation of the linker and building block components.
“With CMRT, we have maintained certain key characteristics from earlier work, but took advantage of the lessons we learned through a myriad of internal and collaborative drug discovery projects to incorporate a number of new aspects that overcome the limitations of the fi rst generation macrocycle technologies,” explained Dr. Thomas. “As such, our strategy combines the best from the past with several novel fundamental design concepts to make CMRT a powerful and versatile approach with defi nite advantages for macrocyclic drug discovery.”
Previous research from the Cyclenium team, while at Tranzyme, was highly successful resulting in the fi rst two synthetic small molecule macrocycles to progress into late stage clinical trials: ulimorelin, an intravenous ghrelin agonist for postoperative gastrointestinal (GI)
figure 3a
recovery, which completed Phase 3 investigation, and TZP-102, an oral ghrelin agonist for GI motility disorders such as diabetic gastroparesis, which reached the end of Phase 2b.
For IRICoR, this latest collaboration is an extension of its interest in the growing macrocycle area, as it is already involved in a partnership, funded by Merck Canada, with Encycle Therapeutics, a biotechnology start-up founded by Dr. Andrei Yudin of the University of Toronto and MaRS Innovation, to develop an orally-bioavailable macrocycle drug to target integrinα4β7 which is involved in the infl ammatory process in a number of diseases, most notably for infl ammatory bowel disease.
“Collaborating with Cyclenium is a natural fi t for our business model,” according to Steven J. Klein, Ph.D., vice-president, business development at IRICoR. “We had a previous successful collaboration with Helmut and his team while they were at Tranzyme. We plan to initiate our new research effort together by including the Cyclenium QUEST Library™ in a number of upcoming HTS campaigns for novel targets in oncology and immunology, and in particular for PPI-based screens.”
IRICoR’s main objective is to rapidly translate highly innovative scientifi c projects from IRIC, UdeM and various centres into high value novel therapies in oncology, immunology and related indications through strong partnerships with the private sector, thereby effi ciently bridging the innovation translation gap between early stage academic research and industry (Figure 3).
IRICoR is a fully-integrated drug discovery and commercialization centre, with one of the largest industry-experienced academia-based medicinal chemistry groups in Canada. In addition to the collaborations with Cyclenium and Encycle Therapeutics, IRICoR has numerous active drug discovery partnerships with a number of companies, including Bristol-Myers Squibb, Merck, Pfi zer, Pharmascience, and Domain Therapeutics.
“In addition, we have several ongoing drug discovery and development projects with the Centre for Drug Research and Development, MaRS Innovation, and Amorchem,” continued Dr. Klein. “We look forward to a long and productive collaboration with Cyclenium.”
Given the exciting potential and largely unexplored nature of the macrocycle space, it can be expected that additional collaborative efforts to take advantage of the particular expertise of organizations with an established presence in this research area, like Cyclenium and IRICoR, will continue to appear over the next couple of years.
References
1. Diggers, E.M.; Hale, S.P.; Lee, J.;
Terrett, N.K. Nat. Rev. Drug Disc. 2008, 7, 608-624. 2. Marsault, E.; Peterson, M.L. J.
Med. Chem. 2011, 54, 19612004. 3. Terrett, N.K. Drug Disc. Today
Tech. 2010, 7, e97-e104. 4. Bionda, N.; Cryan, A.L.; Fasan, R.
ACS Chem. Biol. 2014, 9, 20082013. 5. Bashiruddin, N.K.; Suga, H. Curr.
Opin. Chem. Biol. 2015, 24, 131–138.
To see this story online visit
http://www. laboratoryfocus. ca/?p=2790
b y s tuart r ay, t echnical d irector, s eward l td feature
Preparing for Food Safety
In the latter part of the 20th century, the food industry has evolved in response to the consumer demand for even greater convenience and utility.
Frozen foods, chilled foods and a variety of other manufacturing techniques were further developed to deliver to consumers’ requirements. This was all accompanied by an increase in the risk posed by microbial contaminants to consumer safety and to the survival of food manufacturers.
Food poisoning and spoilage in the 21st century can now lead to food manufacturers’ bankruptcy and the destruction of hard fought for reputations of quality and safety. Unfortunately, the solution will not be the elimination of risk as the variables and possibilities of contamination from “farm to fork” are so myriad. The fact remains that a single breach can be catastrophic. Instead, the food industry as meticulously as it can, both economically and technically, continues to strive to reduce the risk with the microbiological monitoring of products and processes.
Consequences
Reports posted by the Canadian Food Inspection Agency in Ottawa for the first month of this year alone highlight the pressure the food industry is under to guarantee the safety of food. Two of the most virulent and deadly species, Salmonella and Listeria have already made an appearance in vegetables and health food products, showing that it is not just eggs, soft cheeses and chicken that present a potential threat to human health. New threats and old threats appear to defy our efforts to get ahead.
An international issue
across international borders. However, farming practices and permissible interventions in the food chain such as the use of antibiotics vary enormously. As a result food safety practices can affect international trade and reduce access to international markets because these practices are not harmonized.
The trade agreement between the European Union (EU) and the U.S., The Transatlantic Trade and Investment Partnership (TTIP), has raised a number of contentious issues including the use of antibiotics. The public is, so far, reassured by statements made by the Food Standards Agency that antibiotic and growth hormone treated meat products will not be forced onto the plates of EU citizens.
The Canada-European Union Comprehensive Economic and Trade Agreement (CETA) adopts a more harmonized approach with existing EU standards. The EU rules on food safety are designed to protect human life and health, as are the current Canadian standards. Broadly, imports of foodstuffs must comply with general conditions including traceability, hygiene and microbiological criteria. Specific rules apply on genetically modified food and feed, bio proteins and novel foods and the use of antibiotics and pesticides.
Countries in the Far East keen to access western markets have found that applying accepted western testing and hygiene practices to export food products have made EU and North American markets easier to access. That all said, the key focus of food hygienists still remains on protecting consumers at home where new and unpleasant surprises often fill the headlines.
feature
Unpleasant surprises
A recent survey of chicken meat purchased from major UK retailers has demonstrated the ubiquitous presence of campylobacter species awaiting the unwary or poorly skilled cook. The project was undertaken by the Food Standards Agency (UK) and used both public and private microbiology laboratories to produce the data. The samples processed were chicken skin and sponge swabs taken from chicken carcasses. The FSA is working with government and industry to try to reduce the incidence of campylobacter in chicken meat by 2015, a target the report suggests they will struggle to achieve.1
In order to process swabs and skin prior to microbiological analysis within the FSA campylobacter project, it was necessary to maximize microorganism recovery at the pre-enrichment phase to obtain reliable and reproducible analytical results within given limits and tolerances. The protocol adopted also stressed the need for preventing cross contamination between samples. The homogenisation technique used therefore needed to address both issues. This was achieved by using the Stomacher® laboratory paddle blender which ensured effi cient circulation of the sample and buffer within the Stomacher® bag to maximise organism recovery and enable smaller subsamples to be taken for fully representative analysis of the whole. The sponge swab technique followed by extraction in the Stomacher® has been shown to be a superior method to traditional swab sticks generating a more representative result.2
If elimination of campylobacter is proving a struggle, then close monitoring and epidemiological studies will be keeping microbiologists busy for the foreseeable future.
Rapid methods
The traditional techniques of horizontal isolation of campylobacter are reliable but slow. New real time PCR techniques require shorter pre-enrichment following Stomaching. The possibility of reducing the time to 24 hours allows the possibility of processors being able to clear products before shipping. However, the reliability of the fi nal result still depends entirely on the quality of the sample provided, whatever the speed or sophistication of the method. A study of this technique applied to salmonella in chicken demonstrates the advantages of a rapid and reliable method.3
Sample size matters
An approach recently adopted by the FDA in the U.S. has addressed the statistical disadvantage the microbiologist has to work with by increasing the sample size to up to 375g. These methods, which can be found in the Bacteriological Analytical Manual , have gained favour beyond the U.S. jurisdiction and have been adopted in Australia and South Korea.4 The largest sample volumes apply to meat products and not only applied to poultry but also red meat and in particular for the analysis for e. coli 0157.
The problem
Microbiology as a science has a problem. The techniques used whether they be the latest DNA probe technology or the traditional techniques, which Pasteur himself would not be unfamiliar with, are dealing with the detection of life. Food materials are inherently variable and microorganisms unpredictable. Therefore, it is essential that this variability, both within and between samples, is minimized as far as possible prior to microbiological analyses with proper sampling and also sample preparation techniques.
The solution
Sample preparation is a critical step in all food microbiology globally. High quality sample preparation delivering subsamples that are fully representative of the whole is vital to the ultimate delivery of good quality, accurate results and is a key consideration in food microbiology. To borrow a phrase from the computer industry, “garbage in, garbage out.” No matter how sophisticated your analytical technique, without a good quality sample the result will be meaningless.
References:
1. https://www.food.gov.uk/sites/ default/fi les/campylobacter-survey-q2-report.pdf 2. Thom K.A. et al.. Comparison of swab and sponge methodologies for identifi cation of Acinetobacter baumannii from the hospital environment. Journal of Clinical Microbiology 2012, 50(6):2140. 3. http://tools.lifetechnologies.com/ content/sfs/manuals/4476867A. pdf 4. http://www.fda.gov/Food/Food-
ScienceResearch/Laboratory-
Methods/ucm072616.htm
To see this story online visit
