We are initiating an interdisciplinary research program, aiming to combine modern advances in organic chemistry and molecular biology for examining issues of pertinent medical significance. As the key long-term direction, we are interested in applying the principles of molecular recognition toward exploring orthogonal antitumor, antiviral, and antibacterial strategies, such as inhibition and potentiation of protein-protein interactions, sequence-specific binding to RNA and DNA, site-specific proteolysis, etc. Toward these goals, this program will develop highly integrated strategies for diversity generation, functional selection and characterization of synthetic and biosynthetic molecules with unique properties. The projects in the Savinov laboratory will therefore rely on a wide repertoire of chemical and biological tools and can be initially divided into three interdependent directions:

1. Generation and Processing of Molecular Diversity for Probing Cellular Mechanisms. The key post-genomic challenge requires means of determining and selectively perturbing activities encoded by genes. By exploiting tools of combinatorial chemistry and biology, we intend to gain access to diverse pools of modular small-molecular-weight probes of protein function. These will range from cyclic peptides, accessible biosynthetically as million-member libraries, to synthetic oligomers, possessing properties inaccessible by the former, such as chemical stability, unlimited functional composition, and receptor-independent cellular uptake. Armed with the necessary level of diversity, we can conduct powerful searches toward individual molecules, capable, for example, of perturbing protein-protein interfaces, a major challenge in the drug development area.

2. Development of Functional Genetic Assays: The difficulties associated with structural and functional stability of proteins and their fragments outside of cellular context suggest that in vivo techniques for characterization of intracellular interactions could be highly advantageous, especially in high-throughput applications. A living cell provides a convenient mini-compartment capable of physically insulating a target protein, a modulator (enzyme, polypeptide aptamer, or a small molecule), a responsive reporter system, and genes, directing the synthesis of both targets and effectors. Reporters can induce a unique phenotype, identifiable through screening, or recover certain deficiency, enhancing cell survival potential. The latter, termed genetic selection, is by far more efficient in throughput and is, therefore, best suited for the discovery of rare properties. We plan to adapt genetic selection schemes toward a variety of functional assays, ranging from searches for protein effectors to directed evolution of enzymatic activities.

3. Design, Synthesis, and Application of Sequence-Specific Ligands for Nucleic Acids. Small molecules that bind to DNA with high sequence specificity, irrespective of their secondary structure, are of enormous interest for a wide variety of biological and medicinal applications. This project will develop oligonucleotide mimetics, which are broadly effective in whole-cell experiments, by adapting novel backbone and base-pairing motifs, conducive to both favorable cellular uptake and fine-tuning of structural and physical properties. We will explore a potential application of these oligomers as conditional in vivo transcription modulators, relying on both facilitated cross-membrane transport and sequence-specific annealing.

Education

Selected Publications

• A.R. Horswill, S.N. Savinov and S. J. Benkovic, A systematic methiod foir identifying small-molecule modulators of protein-protein interactions. Proc. Natl. Acad. Sci. USA 2004 , 101, 15591–15596.
• Manjappara U. V.;Savinov, S. N.;Cox, J. M.;Zurawski, J. A.;Smith, A. B.;Chaiken, I. M., Towards high-throughput chemical modification and screening of miniprotein mimetics of CD4 . Biopolymers 2003 , 71 , 357-358.
• Savinov S. N.;Hirschmann, R.;Benkovic, S. J.;Smith, A. B., Investigation of an antibody-ligase. Evidence for strain-induced catalysis . Bioorg. Med. Chem. Lett. 2003 , 13 , 1321-1324.
• Smith A. B.;Savinov, S. N.;Manjappara, U. V.;Chaiken, I. M., Peptide-small, molecule hybrids via orthogonal deprotection-chemoselective conjugation to cysteine-anchored scaffolds. A model study . Org. Lett. 2002 , 4 , 4041-4044.