Combinatorial Peptidomimetics as Antineoplastics

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): We propose to unlock the pharmaceutical potential of cancer targeting peptide ligands identified by phage display. The use of peptides as drugs or delivery adjuvants is limited by their reaction to in vivo conditions. This work brings together expertise in four different fields of science and medicine to develop novel tools and methods for the creation and screening of peptidomimetic targeting molecules suitable for in vivo use. The combination of material science particle technology, peptidomimetic combinatorial chemistry, flow cytometry-based biological testing and clinical medicine promises to yield a general, powerful and scalable screening method for targeting molecules of practical value in the treatment of human disease. The integrated, multidisciplinary and multi institutional solution proposed here is essential to reorganize the gateway to drug discovery based on peptide sequences. This application compliments and extends the existing technology of biopanning phage display for the identification of cancer targeting ligands. We propose to start with peptide sequences identified by other research laboratories as ligands to specific target structures such as tumor endothelium. A peptidomimetic combinatorial library will be prepared based on these, targeting peptide structures. The combinatorial library will contain structures that are unavailable in phage display such as d- amino acids and non-peptide molecules. This approach marries the best characteristics of phage display and traditional pharmaceutical discovery to efficiently create molecules that have both target affinity and in vivo stability. Each member of this combinatorial library will be synthesized on a microsphere with unique properties that allow sorting by flow cytometry. Peptides cleaved from microspheres screened by flow cytometry on the basis of ligand-target recognition will be characterized and synthesized in quantity. These candidate ligands will undergo quantitative biological evaluation of binding strength, binding specificity and stability under simulated in vivo conditions. Stability and probable suitability for in vivo application as targeting adjuvants for pharmacological and radiological interventions or for gene therapies, is overseen in this work by a radiation oncologist with current clinical practice and an active, related research program. The studies described here will demonstrate the proof-of-concept using fundamental scientific principles and will produce examples of peptidomimetic targeting ligands. The products of this work will become preliminary data leading to the discovery and validation of molecular ligands for cancer prevention or treatment intervention consistent with the goal of this PA.