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Education:

• B.S. University of Rome
• M.S. University of Rome
• Ph.D. 1996 Chemistry California Institute of Technology
• Postdoctoral Scripps Research Institute

Overview

Sandro was born and raised in Italy and received a BS/MS from the University of Rome. He received a Ph.D. from the California Institute of Technology in 1996 working with Dennis Dougherty. This was followed by postdoctoral work with Julius Rebek, Jr. at the Scripps Research Institute from 1996 to 1999 where he was a NASA-NSCORT fellow. In the fall of 1999 he joined the faculty of the Division of Pharmaceutical Sciences at the School of Pharmacy, University of Wisconsin-Madison. He currently holds joint appointments in Pharmacy and Chemistry.

My research group's focus is in the general area of molecular recognition and non-covalent forces. Our approach is to use an interplay between experimental and computational techniques to study a variety of interesting problems. More specifically, we use a combination of synthetic organic chemistry, bioorganic chemistry, biophysical chemistry and computational chemistry to explore problems in dynamic combinatorial chemistry, self-assembly, and the physical interpretation and biological importance of intermolecular forces. Molecular recognition has historically developed as the study of the complexation events between a host and a guest. The host is by definition larger than the guest and in some specific cases it can completely encapsulate the guest molecule. As the size of the guest gets larger, the design and synthesis of suitable hosts becomes increasingly difficult until the level of complexity becomes too high to be addressed by rational design. An alternative approach is based on the use of non-covalent interactions to "build" the host through the non-covalent assembly of small, simpler fragments. This process is called self-assembly and it can be defined as the spontaneous formation of higher order structures. Self-assembly plays a pivotal role in nature. Virus assembly and the complex interplay of molecular interactions that regulate the cell machinery are only a few examples of this ubiquitous phenomenon. Self-assembly is the elective tool chosen by nature to build complex structures. As modern cell biology tries to explain the structure and behavior of the whole cell in terms of the biochemical properties of its components, the application of self-assembly concepts to these problems is destined to grow ever larger.

Dynamic Combinatorial Chemistry.
This is an emerging field that combines research in both self-assembly and more traditional combinatorial chemistry. In essence, we make use of libraries of equilibrating species to generate non-covalent complexes able to bind specific molecules through a series of intermolecular interactions. The process of molding of a receptor around a guest is schematically illustrated in Figure 1.



We are currently working on libraries of metal complexes that are able to generate highly selective complexes around biphenyl-based molecules. The key principle guiding these studies is the equilibration of a random library of non-covalent complexes to reach the thermodynamically most stable complex upon template effect by the guest receptor. The host-guest complex is then studied through a combination of mass spectrometry, chromatography and advanced molecular modeling. This approach could in principle be used to generate the optimal host structure for any desired guest. This methodology has practical applications that span from drug delivery to the study of the rules that regulate self-assembly in nature.

Intermolecular Interactions.
We are currently using modified enzyme inhibitors to probe the strength and characteristics of weak intermolecular interactions of fundamental importance in drug design and discovery. Carbon-bound fluorine substituents are present in the large majority of the most recent drugs. It has been proposed that the pharmacological importance of fluorine is partially due to weak interactions with a variety of functional groups including hydrogen bond donors. In order to test this hypothesis and establish the interaction energetics of carbon-bound fluorine in hydrogen bonds we are using fluorinated analogs of known inhibitors of the HIV protease. Our approach consists in replacing hydroxyl groups of the inhibitors, that are known to engage in hydrogen bonds with N-H groups from the protein backbone by fluorine atoms. The variations in the binding behavior of these modified inhibitors relative to the parent species allows precise estimates of the hydrogen bond capabilities of covalently bound fluorine substituents.

RNA Binding and Recognition.
Crystal structures of a variety of complexes between large RNAs and small molecules are known. The usual size of RNA able to selectively bind molecules having a molecular weight of about 100 a.m.u. ranges between 80 and 200 nucleotides. The actual recognition sequence, though, does not exceed twenty nucleic bases. Driving inspiration from the crystal structures of small molecules complexed to in vitro evolved and selected RNAs we are currently designing RNAs no longer than ten nucleotides that are able to fold and selectively bind small molecules such as caffeine and theophylline. The goal of this project is understanding the binding properties of ribonucleic acids. We plan to apply this information to the design of novel self-assembling systems involving nucleic acids among their components.

Work-Related Interests/Research:

Molecular recognition and non-covalent forces

Highlighted Publications:

• S. Mecozzi and J. Rebek, Jr., "The 55% Solution: a formula for molecular recognition in the liquid state, Chem. Eur. J., 4, 1016-1021 (1998).
• D. Mink, S. Mecozzi and J. Rebek, Jr., "Natural products analogs as scaffolds for supramolecular and combinatorial chemistry, Tetrahedron Lett., 39, 5709-5712 (1998).
• R. Meissner, X. Garcias, S. Mecozzi, and J. Rebek, Jr., "Synthesis and assembly of new molecular hosts: solvation and the energetics of encapsulation," J. Am. Chem. Soc., 119, 77-85 (1997).
• S. Mecozzi, A.P. West, Jr. and D.A. Dougherty, "Cation-p interactions in simple aromatics: electrostatics provide a predictive tool," J. Am. Chem. Soc., 118, 2307-2308 (1996).
• S. Mecozzi, A.P. West, Jr. and D.A. Dougherty, "Cation-p interactions in aromatics of biological and medicinal interest. Electrostatic potential surfaces as a useful qualitative guide," Proc. Natl. Acad. Sci., USA, 93, 10566-10571 (1996).