Prof. George Shields, Armstrong Atlantic University

Computational Design of a Small Peptide that Inhibits Breast Cancer

Physical Chemistry Divisional Seminar

Breast cancer is the most common cancer diagnosed in woman and is the second leading cause of cancer death among women, closely following lung cancer.(1) Many breast cancer drugs, like tamoxifen, have limited long term efficacy and often have undesirable side effects, leading researchers to search for new breast cancer drugs.
Alpha-fetoprotein (AFP), an embryo specific serum alpha-globulin glycoprotein, is synthesized by the fetal yolk sac and circulates through the serum of pregnant women.(2) A growth-regulating hormone, AFP has the capacity to both stimulate and inhibit growth, although scientists remain uncertain of the exact pathways involved.(3) In the last several decades, clinical researchers have discovered the anti-estrogenic cancer properties of AFP.(4) A number of studies have since shown its effectiveness as a therapeutic agent to treat estrogen-dependent breast cancer, as well as its ability to prevent pre-malignant foci from developing into breast cancer.(5)
Researchers at Albany Medical College performed studies on AFP, parsing it down to a smaller peptide chain of 34 amino acids that retained the same anti-estrogenic activity as the original molecule.(6) Continuing research attempted to identify smaller subchains of the original AFP molecule that remained active, finding an 8-mer that they named P472-2.(5) Antiestrotrophic activity was then measured in a uterine mouse assay. The original AFP molecule, its 34 amino acid analogue, and P472-2 all showed comparable activity in prohibiting estradiol-induced growth in the uterus. P472-2 has been shown to inhibit estrogen-induced T47D breast cancer cells in culture as effectively as the original AFP molecule.(5)
Information about the pharmacophore has been previously obtained by substituting amino acids in P472-2.(7) Cyclic analogs nine amino acids long have been synthesized that also retain full activity. All efforts to create a peptide under eight residues resulted in the loss of anti-cancer activity. We have used Replica Exchange(8, 9) Molecular Dynamics techniques(10) to model selected active analogs of the linear and cyclic peptides to explore their conformational space. Our results reveal that the peptide's critical region is a four amino acid sequence that has a turn conformation. We present here a new lead compound that shows anti-cancer activity as measured in T47D breast cancer cells in culture and in animal assays (11-13).

This research was supported by DOD, NIH and NSF.

1. American Cancer Society, Atlanta, 2005, vol. 2005, pp. American Cancer Society Website.
2. G. I. Abelev, Advances in Cancer Research 14, 295 (1971).
3. G. J. Mizejewski, Experimental Biology and Medicine 226, 377.
4. H. I. Jacobson, J. A. Bennett, G. J. Mizejewski, Cancer Research 50, 415.
5. F. B. Mesfin, J. A. Bennett, H. I. Jacobson, S. J. Zhu, T. T. Andersen, Biochimica Et Biophysica Acta-Molecular Basis of Disease 1501, 33.
6. G. J. Mizejewski, R. MacColl, Molecular Cancer Therapeutics 2, 1243.
7. L. A. DeFreest et al., Journal of Peptide Research 63, 409.
8. Y. Sugita, Y. Okamoto, Chemical Physics Letters 314, 141.
9. A. Mitsutake, Y. Sugita, Y. Okamoto, Biopolymers 60, 96 (2001).
10. D. A. Case et al. (University of California, San Francisco, 2004) pp. AMBER Version 8 Molecular Dynamics Program.
11. K.N. Kirschner, K.W. Lexa, A.M. Salisburg, K.A. Alser, L. Joseph, T.T. Andersen, J.A. Bennett, H.I. Jacobsen, G.C. Shields, J. Am. Chem. Soc. 129 (2007) 6263-6258.
12. K.W. Lexa et al., International Journal of Quantum Chemistry 107 (2007) 3001-3012.
13. L.C. Joseph et al., Journal of Peptide Research 15 (2009) 319-325.
14. G.C. Shields Future Medicinal Chemistry 1 (2009) 201-212.

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For more information contact Prof. David Sherrill (404-894-4037).

Biographical sketch

George Shields grew up in central New York. He earned a B.S. in Chemistry at Ga Tech in 1981 and enrolled in the master’s program at Tech with the intention of becoming a high school teacher. As an undergraduate he did research in Charlie Liotta’s laboratory. After completing his M.S. in Chemistry in May of 1983 in Tom Moran’s laboratory, he decided to pursue a Ph.D. at Tech, which he completed in March of 1986. His thesis work was in chemical physics in the Moran lab, using Mass Spectrometers to study ion-molecule collisions. He then went to Yale for a postdoc, working in Tom Steitz’s lab, where he solved (with Steve Schultz, a fellow postdoc) the structure of the Catabolite Gene Activator protein complexed with DNA. In August of 1989 he joined the faculty at Lake Forest College, north of Chicago, and spent nine years there, the last two as Chairperson of the department of chemistry. In June of 1998 he moved to Hamilton College, where he has chaired the department until July of 2006. During his tenure as chair at Hamilton enrollments in general chemistry increased by 50%, the number of chemistry majors increased from three to 15 per year, and the number of summer research students in the department increased from four to forty per summer. His current research interests use computational chemistry to investigate atmospheric and biological chemistry. He is the founding Dean of the College of Science & Technology at Armstrong Atlantic State University, in Savannah, GA, a position he has held since July 1 2008. He is involved in a number of initiatives to increase the amount of undergraduate research in computational chemistry, and in his college. This past summer he founded the first summer research program in AASU’s history, with more than 20 professors and 50 students participating, and set up the structure to continue future funding.