With increasing investment into pharmaceutical industry there is a paradoxical decline in the number of new medicines on the market. One of the reasons for this phenomenon is the focus of pharmaceutical companies on small molecules for development of therapeutic agents. Although they are potent inhibitors of target proteins, small molecules are known for their low specificity. Larger and more complex molecules, such as peptides, provide more specific target recognition. However, peptides are unstable and require design of cellular delivery mechanisms. Utilization of structural plasticity of peptide molecules in biological solvents is a novel approach to solve the problems with peptide pharmaceutical agents. In aqueous solutions certain peptides exhibit a distinct beta-hairpin conformation that allows them to assemble into spherical nanostructures. Nanostructures encounter a hydrophobic environment of the plasma membrane, disassemble, insert into the membrane, change their conformation, and inhibit target proteins. I hypothesize that by studying the peptide assembly mechanism into nanoparticles it is possible to formulate a set of requirements for the design of peptides capable to form nanoparticles. The long term goal is to define the requirements for intermolecular interactions between peptides allowing assembly into nanoparticles. Understanding the mechanism of peptide structure transitions will enable development of novel therapeutic nanoparticles capable of performing an encoded sequence of tasks. I shall address the requirements for the design of such peptides by studying the structure of the monomeric peptides, the mechanism of nanoparticle assembly, and the structural changes in the lipid environment. I propose the following specific aims: (1) Determine the structural requirements for the monomeric peptide that allow assembly into nanoparticles using nuclear magnetic resonance (NMR) techniques;(2) Identify the intermolecular interactions responsible for peptide assembly into nanoparticles using NMR, electron microscopy, and dynamic light-scattering;(3) Analyze structural changes that the peptide molecules undergo in the lipid environment by NMR.
This application addresses elucidation of mechanisms of peptide assembly into spherical nanoparticles and structure-based optimization of anti-cancer activity of chemokine receptor CXCR4 inhibitor peptide f22. PEGylated f22 peptide assembles into spherical nanoparticles, inhibits breast cancer growth, and prolongs survival in mouse breast cancer dissipation model. F22 self-assembly into nanoparticles may prevent peptide degradation in the blood stream and provide targeted delivery of f22 to CXCR4 expressing tumors due to the enhanced permeability and retention effect. The knowledge acquired as a result of the proposed research may be applied to the development of novel peptide pharmaceutical agents.
|Tripathi, Abhishek; Gaponenko, Vadim; Majetschak, Matthias (2016) Commercially available antibodies directed against Î±-adrenergic receptor subtypes and other G protein-coupled receptors with acceptable selectivity in flow cytometry experiments. Naunyn Schmiedebergs Arch Pharmacol 389:243-8|
|Evans, Ann E; Tripathi, Abhishek; LaPorte, Heather M et al. (2016) New Insights into Mechanisms and Functions of Chemokine (C-X-C Motif) Receptor 4 Heteromerization in Vascular Smooth Muscle. Int J Mol Sci 17:|
|Banerjee, Avik; Jang, Hyunbum; Nussinov, Ruth et al. (2016) The disordered hypervariable region and the folded catalytic domain of oncogenic K-Ras4B partner in phospholipid binding. Curr Opin Struct Biol 36:10-7|
|Jang, Hyunbum; Banerjee, Avik; Chavan, Tanmay S et al. (2016) The higher level of complexity of K-Ras4B activation at the membrane. FASEB J 30:1643-55|
|Tripathi, Abhishek; Vana, P Geoff; Chavan, Tanmay S et al. (2015) Heteromerization of chemokine (C-X-C motif) receptor 4 with Î±1A/B-adrenergic receptors controls Î±1-adrenergic receptor function. Proc Natl Acad Sci U S A 112:E1659-68|
|Jang, Hyunbum; Abraham, Sherwin J; Chavan, Tanmay S et al. (2015) Mechanisms of membrane binding of small GTPase K-Ras4B farnesylated hypervariable region. J Biol Chem 290:9465-77|
|Chavan, Tanmay S; Jang, Hyunbum; Khavrutskii, Lyuba et al. (2015) High-Affinity Interaction of the K-Ras4B Hypervariable Region with the Ras Active Site. Biophys J 109:2602-13|
|Muratcioglu, Serena; Chavan, Tanmay S; Freed, Benjamin C et al. (2015) GTP-Dependent K-Ras Dimerization. Structure 23:1325-35|
|Lu, Shaoyong; Banerjee, Avik; Jang, Hyunbum et al. (2015) GTP Binding and Oncogenic Mutations May Attenuate Hypervariable Region (HVR)-Catalytic Domain Interactions in Small GTPase K-Ras4B, Exposing the Effector Binding Site. J Biol Chem 290:28887-900|
|Chavan, Tanmay S; Meyer, James O; Chisholm, Luke et al. (2014) A novel method for the production of fully modified K-Ras 4B. Methods Mol Biol 1120:19-32|
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