Joshua Pierce

Training in the application of chemical principles is essential for modern research across a number of disciplines ranging from Chemistry and Biochemistry to Biology, Engineering and Medicine. Acknowledging this need, NC State University has launched a new research and training program called the Chemistry of Life Program (CLP) and initiated an innovative graduate training program, the Chemistry of Life Training Program (CLTP), as a core element. A key aspect of this program is core training, both lecture and experimental, in core chemical biology principles and techniques. This not only facilitates completion of the students������������������ dissertation research, but also lays the basis for career opportunities in academic, government, and industrial research settings. To achieve this, the CLTP has partnered with the Comparative Medicine Institute and Biotechnology Training Program to synergize this program across our campus though at least 4 Colleges and 7 Departments. A trans-departmental Executive Committee will lead the operation of the CLTP and oversee sub-committees focusing on program elements. The specific objectives of the training program are: 1) Ensure technical proficiency and training in responsible and rigorous science; 2) Provide an educational and training experience that is in line with graduate students������������������ expectations for an interdisciplinary future; and, 3) Nurture robust PhD graduation outcomes. Six slots (three in year 1) are requested that will be augmented by four slots (two in year 1) from University resources. The program requirements include a minor in the Chemistry of Life; a course in professional development/ scientific rigor and reproducibility; courses in research ethics; and an annual research symposium/retreat. These requirements are in addition to those associated with the student������������������s particular Department or Program for the doctoral degree. During their two-year appointment to the training grant, trainees will also benefit from an exploratory laboratory rotation program, co-mentorship across disciplines, access to development workshops on topics like research commercialization, and the opportunity to be guided through mentorship of undergraduate researchers on a team science project. This program will also provide a central focus for faculty of the various disciplines involved in this training effort to seek out new opportunities for formal and informal research collaboration as part of the broader CLP program.

This project is focused on the development of novel chemical reactions and approaches to synthesize complex natural products in order to generate lead compounds for chemical biology and medicinal chemistry studies. Through these efforts we plan to make substantial contributions to the development of novel treatments for a variety of disease areas including infections disease, cancer and pain.

Heterocycles are key components of bioactive natural products, materials for energy transport, ligands for catalysis, and countless other applications where small organic molecules are employed; therefore, their preparation and study has been the target of synthetic chemists since the advent of organic chemistry. Given this rich history many heterocyclic scaffolds are straightforward to prepare, with some heterocycles such as triazoles even being prepared via click reactions in in-vivo settings. Synthetic limitations remain in the preparation of more functionalized heterocyclic scaffolds, particularly for compounds with non-natural functionalities. Novel synthetic approaches to heterocycles have the potential to enable access to previously inaccessible structures, expedite the synthesis of known molecules and shed light on new reaction pathways and chemical reactivities applicable to other areas of synthesis.

We are proposing an innovative undergraduate research program at the Chemistry:Life Science interface across NC State, building on the success of a unique team-based undergraduate research program being developed in the Comparative Medicine Institute, referred to as the SIRI program (Summer Interdisciplinary Research Initiative). This program has already led to a NIH T34 grant in an orthogonal translational research area, and is primed to serve as the foundation for a Beckman Scholars Program. Although building on this successful framework, this program will be distinct and tailored for this call. NC State������������������s Beckman Scholars Program will set itself apart nationally by leveraging team science (faculty co mentors), a mentoring of mentors program, and communication and leadership programs to train students across traditional barriers while having them participate in innovative research projects at the Chemistry:Life Science interface. The focus on faculty co-mentors, engaged graduate/postdoc mentors and cutting edge, vetted research projects positions us well to compete successfully to bring the Beckman Scholars Program to NC State.

NC State is the largest university in North Carolina, with nearly 34,000 students, including 8,500 graduate students. Approximately 56% of all students are men, and 44% are women; approximately 16% are members of underrepresented groups. Yet, the number of programs focusing on preparing highly qualified UR students for PhD or MD/PhD is low (1). There is, therefore, a strong need for this program at NC State. In addition, team or interdisciplinary science has become an integral component of biomedical research. Yet most training programs still rely on the traditional single discipline training. This U-STAR program combines the strengths of a university-wide biomedical institute, the Comparative Medicine Institute (CMI), and the University Honors Program at NC State in order to train the next generation of UR biomedical scientists in a rigorous inter/trans disciplinary environment. Major program components include: 1) A pre-U-STAR feeder program designed to introduce students to the program and to the unique skills required to carry team science; 2) A ����������������Mentor-the-Mentor��������������� program for Graduate students, Postdoctoral Fellows and Junior Faculty mentoring U-STAR Scholars; 3) A U-STAR program that provides rigorous hands-on research mentoring in inter/transdisciplinary sciences; and 4) Professional development activities that include career and academic advising, seminar series, preparation to present orally and in poster format, workshops on scientific communication, introduction to existing T32 programs at NC State and at our partner institution, UNC Chapel Hill, and assistance with application to graduate school. Our overall goal is to enroll 10 new U-STAR scholars each year, 70% of which will matriculate in a biomedical sciences PhD or an MD/PhD program.

The development of novel chemical reactions for the synthesis of molecules with potent biological activities and unprecedented structures is a pressing need for the evaluation of such compounds as medicines. Our research focuses on the synthesis of complex natural products that have shown the potential to serve as antimicrobial and anticancer agents. In addition to developing chemical reactions that will be broadly useful in organic and medicinal chemistry we also target analogs of the parent natural products that bear simplified structures and improved activity and selectivity profiles. Through these efforts we aim to prepare chemical probes and therapeutic lead structures to tackle the developing problem of antimicrobial resistance and the ongoing fight against aggressive human cancers.

The monanchocidins are a family of marine natural products that show potent activity against a number of cancer cell lines. We are developing synthetic strategies to assemble these molecules to allow for their study as chemical probes. These probes will allow for the study of a number of biological processes important for cancer and HIV/AIDS and potentially lead to lead molecules for drug development projects.

This proposal describes the optimization and biological evaluation of novel compounds for the treatment of ESKAPE pathogens, particularly MRSA, MRSE and A. baumannii drug resistant strains. In addition to the research aims of this proposal there is a commercialization component in which a commercialization advisor will aid in a go/no go decision for the further development of this technology.

Clinical resistance has been observed in all classes of antibiotics currently in use and no new classes of broad-spectrum antibiotics have entered the market in almost 50 years. As a result, previously treatable infections have become a significant threat to human health, giving rise to an urgent need for novel antimicrobial drug scaffolds.1 To this end, nature has been a fruitful source of chemically diverse,biologically active molecules. In fact, 50% of new drugs and 70% of new antibiotics worldwide from 1981-2010 have been either natural products or derivatives thereof.

The work outlined in this proposal describes novel synthetic chemistry aimed to provide improved synthesis of important compounds for the construction of biologically active molecules.