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Sanku Mallik's Research
(1) Design of Isozyme-Selective Inhibitors for Matrix Metalloprotienase-9:
Over-expression of matrix metalloproteinases has been associated with a variety of human diseases, e.g., arthritis, cancer, cardiovascular diseases etc. Amongst the MMPs, MMP-2 and -9 have been found to overexpress in tumors of breast, prostrate, pancreas and ovary. In addition, these two enzymes are involved in angiogenesis, invasion and metastasis of tumors and in the immune response to cancer. Most of the reported inhibitors for MMPs are broad-spectrum inhibitors and have severe side effects. In contrast to the broad-spectrum inhibitors, the selective inhibitors are very promising as anti-metastatic agents.
In collaboration with Prof. D. K. Srivastava (Biochemistry, NDSU), we have recently developed a highly-promising strategy for inhibitor design, called “two-prong” approach. In this approach, one part of the inhibitor binds to the active site region and the other part binds to the surface-exposed histidine residues. Since the surface-exposed histidine patches are not conserved among MMP isozymes, our contemplated “two-prong” inhibitor design approach will produce isozyme-specific inhibitors for MMP-9. The specific aims of this proposal are summarized below.
(2) Fabrication of hybrid liposomes with triple-helical collagen peptides for targeting to the matrix metalloproteinase-9:
In collaboration with Prof. D. K. Srivastava ( North Dakota State University), this project aims to develop novel, triggered, liposomal drug delivery methods activated by an MMP-9. Hybrid, liposomes (incorporating lipids and lipo-peptides) are prepared encapsulating an inhibitor for the enzyme. The non-polymerized lipids present a peptide sequence on the liposome surface to be recognized and subsequently cleaved by the enzyme. The peptide cleavage will destabilize the non-polymerized domains of the liposomes, resulting in the formation of holes and “uncorking” of the liposomes. The encapsulated inhibitor will be released rapidly from the liposomes, inhibiting MMP-9. The peptide sequence can be suitably altered when inhibition of another MMP is necessary. This project combines the advantages of targeting and triggered release of unpolymerized liposomes with stability and rapid release property of hybrid liposomes to deliver drugs to a chosen MMP.
(3) Development of Chemical Receptors for Proteins Based on Polymerized Liposomes:
This project aims to fabricate highly selective, robust, chemical receptors for proteins employing polymerizable mixed liposomes. Nature uses antibodies to bind to a protein strongly and selectively. The goal of this project is to develop effective “synthetic antibodies”. We prepare liposomes with polymerizable neutral lipids (zwitter ionic) as the major constituent. Other component lipids are metal-chelating and with charged head groups. After fabrication, these liposomes (in the unpolymerized state, above the gel-transition temperature) will be allowed to interact with the template protein. The metal ions on liposome surface will orient complementary to the pattern of surface-exposed histidines and/or acidic residues (Asp/Glu) of the enzyme. Quaternary ammonium headgroups on the liposomes will be positioned by acidic amino acid residues (Asp, Glu) on the protein surface. Amino acid side chains of the template protein capable of forming hydrogen bonds (e.g., Ser, Thr, Lys, Asn, Gln and Arg) will interact with the primary amine moieties on the liposome. The result of this equilibration step is the creation of a pattern of metal ions, charges and hydrogen bonding sites on the liposome complementary to the surface pattern exhibited by the protein of choice. We polymerize the resultant liposomes to prepare selective receptors for the protein of choice.
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