University of Cincinnati
College of Pharmacy
3225 Eden Ave.
P.O. Box 670004
Cincinnati, OH 45267-0004

Email James

Honors
Funding
Publications

My laboratory is currently involved in developing new compounds that affect skin pigmentation and protect melanocytes from damage resulting from exposure to UV radiation. These compounds are based on the structure of a peptide hormone called alpha-Melanocortin that is produced by cells of the skin called melanocytes. The normal function of alpha-Melanocortin in these cells is to cause pigmentation (i.e. tanning) of the skin upon exposure to sunlight. This is a protective mechanism to prevent damage to skin by harmful solar radiation. Compounds that block the action of alpha-Melanocortin would be expected to lighten skin while those that mimic its action would darken skin. There are skin disorders that result in either unpigmented regions or over pigmented regions of skin. Analogs of alpha-Melanocortin that can enhance pigmentation or reverse excessive pigmentation would be useful in treating these conditions. We have developed analogs of alpha-Melanocortin that appear to be specific for both of these actions and are more stable than the parent molecule.

In collaboration with Prof. A. Balasubramaniam of the Department of Surgery, we are working on the deisgn and synthesis of Peptide YY analogs. Peptide YY and its homologous hormones exhibit a variety of central and peripheral effects mediated by several receptors denoted as Y1, Y2, Y4 and Y5. All these hormones and their receptors play a crucial role in the regulation of food intake and the maintenance of energy homeostasis. Our efforts have been toward the development of tripeptide (Y5), pentapeptide (Y1 and Y4) and dodecapeptide (Y2) based potent and receptor selective compounds that inhibit food intake and therefore have potential in the treatment of obesity.

Two other projects involve the design and synthesis of protein kinase inhibitors. One involves inositol 3-phosphate kinase alpha or 110alpha where we have designed a series of potential inhibitors via virtual screening of a library in the enzyme active site. This has involved building (in collaboration with Matt Wortman) a homology model of this enzyme since no X-ray crystal structure is currently available. We are now in the process of synthesizing compounds from this screen that have been predicted to be have greater selectivity for this isoform.

A second kinase inhibitor project involves calmodulin activated kinase 2 gamma (CaMKIIdelta). Again we are building a homology model and screening compounds from a chemical library.

Other areas of interest in my laboratory include: computer assisted drug design (QSAR, virtual screening, homology modeling), synthesis of non-natural amino acids, and prodrug design.



Honors:
Delta Sigma Theta Epsilon Award for Excellence in Teaching (Rutgers University) 1984
Rho Chi Society (Beta Nu Chapter), Faculty Excellence Award, 1994, 1992, 1989
Phi Lambda Sigma Pharmacy Leadership Society, 1992
University of Cincinnati, First Professional Year Faculty Excellence Award, 2004, 2005



Funding Support
Co-PI with Prof. Zalfa Abdel-Malek, "Discovery of Alpha-MSH Analogs for Skin Cancer Prevention", NIH, 2006-2010.

PI, Design, Synthesis and Bioassay of Selective Phosphoinositide 3-Kinase Alpha Inhibitors, College of Pharmacy, Pilot Project Funds.

Pending:
Co-Investigator with Prof. A. Balasubramaniam, "Development of Novel Peptide YY Ligands to Control Obesity", NIH.


Publications

1:

Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, Todorovic A, Koikov LN, McNulty JC, Jackson PJ, Millhauser GL, Schwemberger S, Babcock G, Haskell-Luevano C, Knittel JJ Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity. FASEB J. 2006 Jul;20(9):1561-3. PMID: 16723376 [PubMed - indexed for MEDLINE]

2:

Balasubramaniam A, Mullins DE, Lin S, Zhai W, Tao Z, Dhawan VC, Guzzi M, Knittel JJ, Slack K, Herzog H, Parker EM Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. J Med Chem. 2006 Apr;49(8):2661-5. PMID: 16610810 [PubMed - indexed for MEDLINE]

3:	Koikov LN, Ebetino FH, Hayes JC, Cross-Doersen D, Knittel JJ End-capping of the modified melanocortin tetrapeptide (p-Cl)Phe-D-Phe-Arg-Trp-NH2 as a route to hMC4R agonists. Bioorg Med Chem Lett. 2004 Oct;14(19):4839-42. PMID: 15341935 [PubMed - indexed for MEDLINE]

4:

Koikov LN, Ebetino FH, Solinsky MG, Cross-Doersen D, Knittel JJ Analogs of sub-nanomolar hMC1R agonist LK-184 [Ph(CH2)3CO-His-D-Phe-Arg-Trp-NH2]. An additional binding site within the human melanocortin receptor 1? Bioorg Med Chem Lett. 2004 Aug;14(15):3997-4000. PMID: 15225714 [PubMed - indexed for MEDLINE]

5:	Stanton DT, Mattioni BE, Knittel JJ, Jurs PC Development and use of hydrophobic surface area (HSA) descriptors for computer-assisted quantitative structure-activity and structure-property relationship studies. J Chem Inf Comput Sci. ;44(3):1010-23. PMID: 15154770 [PubMed - indexed for MEDLINE]

6:	Koikov LN, Ebetino FH, Solinsky MG, Cross-Doersen D, Knittel JJ Sub-nanomolar hMC1R agonists by end-capping of the melanocortin tetrapeptide His-D-Phe-Arg-Trp-NH(2). Bioorg Med Chem Lett. 2003 Aug;13(16):2647-50. PMID: 12873485 [PubMed - indexed for MEDLINE]