The University of Arizona BIO5 Institute and Department of Biochemistry & Molecular Biophysics announce the 2008 summer and academic year industry internships at sanofi-aventis Combinatorial Technologies Center.

The combinatorial technologies center in Tucson serves as an integrated lead discovery engine, delivering novel lead compounds for challenging targets and creating compound libraries that coordinate with therapeutic area needs and complement sanofi-aventis' existing compound collection. More than 70 employees with expertise in such areas as chemistry, biology, information systems, and library development work at the combinatorial technologies center.

Summer internships:

1. Semester-basis, 10 hours/week, students expected to also maintain a .25 GA-ship
2. Interns selected competitively from the group of summer interns

Graduate and undergraduate students who have advanced research training will be considered based on the basic requirements listed below. Project descriptions follow. Interested students who meet the requirements must submit the following materials by 5:00pm March 14th, 2008:

1. Cover letter
2. Copy of CV
3. Letter of recommendation from primary faculty advisor, demonstrating that the advisor is supportive of the internship experience
4. An additional letter of recommendation from one other member of the student's advisory committee for graduate applicants or another research mentor / instructor for undergraduates

Kevin Hall, Director, Research Training & Career Development, BIO5 Institute, P.O. Box 210240 or contact us with questions at jkh@email.arizona.edu.

Biology

The biology internship candidate should have carried out experiments with biochemical or cellular systems in a research or industrial setting. Experiences in a non-classroom laboratory, and experience in experimental design, are critical. Experience with sterile technique is a plus. Preference will be given to candidates who have had their own research project and can discuss the rationale for their project and the techniques they have selected & used.

Chemistry

The chemistry candidate should have knowledge of general organic chemistry and basic analytical techniques used to characterize reaction products, plus some practical experience with functional group inter-conversions, protecting group strategies, and reaction mechanisms. Beginning expertise in knowledge of certain fields within chemistry (such as organometalic reactions, multi-component reactions, microwave techniques, specialty linkers) is a plus. Experiences in a non-classroom laboratory, and experience in experimental design are critical.

Analytical Chemistry

Candidate should have a fundamental knowledge of chromatographic principles, mass spectrometry and other techniques for the analysis of small molecules. Experience with common laboratory procedures is essential. Some practical experience with HPLC or mass spectrometry in classroom laboratories or research laboratories is useful. Familiarity with computer usage and common software packages such as Excel, PowerPoint, Word, and scientific/mathematic software is essential. Students who have demonstrated the ability to perform independent work in a laboratory setting would be greatly preferred.

All candidates must demonstrate health, safety and environmental consciousness, be able to follow all health, safety and environmental regulations, standards and internal requirements. Ability to work well in a team environment and accept direction is essential.

CHEMISTRY

Multi-step synthesis of protected intermediates used in synthesis of combinatorial libraries
   Research plan for 3-month period includes multi-step synthesis of protected intermediates that could be used in synthesis of combinatorial libraries. Synthesis would start from commercially available synthons. The ultimate goal is to obtain 5-10g of novel and chemically stable intermediates that would be tested in ongoing chemistries and would become part of our new combinatorial libraries. Besides this major goal, a parallel research on design and synthesis of safety-catch linkers would be carried out. State-of-the art oxygen activated, water cleavable linker is proposed and all structural elements would be explored.

Exploration of solid phase chemistry for libraries on solid support
   Exploration and development of solid phase chemistries for library synthesis. If successful exploration, the student will develop and optimize the chemistry up to library production.
   Exploration of 'Natural product like libraries'.
   Optimization of 3 component reaction for the preparation of unique scaffold. The intern will then optimize the purification of the desired compound and complete the preparation of a small solution phase library

LIBRARY PRODUCTION

Optimization of parallel HPLC system with MS detection
   Research plan for 3-month period includes multi-step synthesis of protected intermediates that could be used in synthesis of combinatorial libraries. Synthesis would start from commercially available synthons. The ultimate goal is to obtain 5-10g of novel and chemically stable intermediates that would be tested in ongoing chemistries and would become part of our new combinatorial libraries. Besides this major goal, a parallel research on design and synthesis of safety-catch linkers would be carried out. State-of-the art oxygen activated, water cleavable linker is proposed and all structural elements would be explored.

ANALYTICAL DEPARTMENT

Synthesis of arrays of compounds and evaluation of SCF extraction.
   The proposed research involves optimization of hardware and software to increase the reliability of a parallel LC/MS system. An industry challenge is increasing the throughput of LC/MS analyses without sacrificing quality. Building upon the successes of previous interns, the research will cover the final stages of bringing the parallel LC/MS system to production readiness including optimization of chromatographic and data processing methods. Performance testing versus conventional and high-throughput serial methods is part of the project. Collaboration is expected with Analytical Chemistry and Information Sciences staff and the software vendor. All instrumentation and software is state-of-the-art.

Improvement of analytical deconvolution of complex samples from combinatorial libraries
   One of the inherent challenges in Lead Discovery employing high-throughput screening is the identification of bioactive components from complex samples. The successful intern will assist in developing new hardware (LC/MS/fraction collection) and software for performing this task as well as working with "live" samples to empirically determine the structures of bioactive components. Positioned in the discovery process at the initial interface of synthetic chemistry and screening biology, this project will give a true experience of medicinal discovery through collaboration with local chemists, biologists, information scientists and the software vendor. All equipment is state-of-the-art.

Medium-throughput quantitation of small molecules via LC/MS/Chemiluminescent nitrogen detection
   Owing to scale limitations and inaccuracies in handling, concentrations of liquid samples employed for Lead Discovery can vary by as much as ten-fold. Consequently rapid methods for determining solution concentrations of analytes have been developed. One such method takes advantage of chemiluminescent nitrogen detection (CLND). This practical internship will provide real experience working in an analytical chemistry lab dedicated to medicinal discovery. Through collaborations with synthetic chemists and biologists, the successful intern will employ LC/MS/CLND methodology to work as a team member on current Lead Discovery efforts using state-of-the-art hardware and software.

BIOLOGY DEPARTMENT

Biological characterization of small molecules specifically targeting cancer cells
   We are characterizing small molecules to identify those that may be useful in specifically targeting cancer cells. We are interested in pathways that may be more vulnerable in cancer cells than in normal cells. We have used whole cell and biochemical approaches to identify interesting molecules and we have identified a class that appears to affect the ability of cancer cells to progress through the cell cycle. These compounds may induce apoptosis and appear be to be directed at pathways which are altered in many cancers. We are currently developing assays to gain further insight in the mechanism of action of our compounds and to help identify a structure activity relationship in some of our compound series. An intern will work in the modern industrial laboratory and gain experience in assay development and with equipment for and high-throughput screening.

Discovery of activity of small molecules through automated high-throughput screening of large combinatorial libraries
   Student intern will be involved in an adaptation and validation of cellular and molecular assays to the high-throughput screening, execution of screening campaigns on robotic stations and conformation and evaluation of activity of compounds in follow up assays. Student will work with state of the art robotic and screening equipment. Computer proficiency and capability and willingness to work with lab instrumentation is essential for this project.

Cellular responses to chemokines
   Chemokines are a large family of small proteins that help to coordinate inflammatory processes, and they constitute a class of target for modulating various diseases. The local research center of sanofi-aventis has discovered several classes of small molecule antagonists that affect different chemokines. An intern is sought to work on model systems of the biological responses to chemokine stimulation using both engineered and primary cell types.