Professor of Chemistry
Ph.D. University of Milan, 1987
(Physical and Biophysical Chemistry)
The Varani research group studies the interactions between proteins and nucleic acids to understand how proteins bind nucleic acids at the physical chemical level, with the aim of being able to rationally design new peptides and small molecule drugs that are able to control human regulatory networks or repress viral replication. Members of the group use spectroscopic (NMR), crystallographic, computational and biochemical techniques to achieve this goal.
Gene expression is central in biology - the human genome contains only five times as many genes as yeast, but 100,000 RNA-coding genes and complex networks regulating gene expression multiply the diversity of our genome. Different genes are copied into messenger RNA differently, and these mRNAs are then chemically processed, localized in the cell, and translated into proteins differently. These processes are the reason why highly evolved tissues, such as those in the brain, are so astonishingly complex. Since the majority of human genetic variation occurs outside protein coding regions, gene expression is also essential to understand why we respond differently to treatment or are susceptible to certain diseases.
Proteins that bind to nucleic acids play critical roles in disease progression. Misregulation of gene expression pathways or their exploitation by pathogens leads to human disease. The Varani group is studying how viral and human proteins and RNA interact with each other, in order to understand how viruses such as HIV exploit the human gene expression machinery to replicate.
(NMR structure of a peptidomimetic compound bound to HIV TAR RNA)
Control of gene expression depends on molecular recognition events that remain to be understood at a fundamental physical chemical level. The fundamental biological processes described above are carried out by specific RNA structures and DNA sequences and by the proteins that interact with them. If we want to understand gene expression and its regulation, it is necessary to understand at the atomic level how protein and nucleic acids interact with each other. This task requires determining atomic structures of the proteins and RNA molecules and of their complexes, and to determine the thermodynamic and kinetic signature associated with complex formation. It is only by understanding why a certain protein binds a specific RNA or DNA sequence, and not any other (specificity), that it is possible to understand how and when a specific gene is activated. By achieving this aim, it will increasingly be possible to use sophisticated computational approaches to design peptides or small molecules to control these processes.
The long-term goal of the research group is to design peptides with new activities and synthesize new drugs to treat infectious and chronic disease. If we harness this knowledge, it will be possible to rationally design new peptides and small molecule drugs that control gene expression networks. This is the fundamental goal of the Varani research group.
(NMR spectrum of the complex between a peptidomimetic inhibitor of HIV replication and the HIV RNA regulatory element it targets in the cell)
A wide range of experimental and computational techniques are applied. Students and post-doctoral fellows in the group use NMR spectroscopy, X-ray crystallography, computational biology, molecular biology and biochemical techniques: often all of these tools are used by a single student to tackle a specific problem. By exploiting new NMR methods, and interfacing closely with computational biology and theoretical chemistry (sequence analysis, homology modeling, structure-based drug design), the Varani group aims to determine structures of increasing complexity and to measure new experimental properties of biological interfaces.
(Fluorescence microscopy in living cells used to study cell penetration properties and nuclear distribution of a peptidomimetic inhibitor of HIV replication)
M. S. Lalonde, M. A. Lobritz, A. Ratcliff, Z. Athanassiou, Mudit Tyagi, J. A. Robinson, J. Karn, G. Varani and E. J. Arts Dual inhibition of HIV-1 reverse transcription and mRNA transcription by a conformationally constrained peptidomimetic that binds the Tat-transactivating response element (TAR) in HIV-1 genomic RNA PLOS Pathogens 7e1002038 (2011)
M.-K. Lee, M. Gal, L. Frydman and G. Varani Real-time multidimensional NMR folding the adenine-sensing riboswitch with second resolution PNAS 107 9192-9197 (2010)
B. M. Lunde, S. L. Reichow, M. Kim, S. Buratowski, A. Meinhart and G. Varani, Recruitment of transcription termination factors by cooperative interactions with the RNA polymerase II C-terminal domain Nature Struct Mol Biol 17 1195-1201(2010)
A. Davidson, T. C. Leeper, Z. Athanassiou, K. Patora-Komisarska, J. Karn, J. A. Robinson and G.Varani Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein Proc. Natl. Acad. Sci. USA 106 11931-11936 (2009)
B. M. Lunde, C. Moore and G. Varani RNA-binding proteins: modular design for efficient function Nat Rev Mol Cell Biol. 8 479-490 (2007)