Gabriele Varani

Professor of Chemistry
(Physical, Biophysical, Ph.D., University of Milan, 1987)

(206) 543-7113
varani@chem.washington.edu
Research group website

Research Interests

The Varani research group study how proteins and nucleic acids interact with each other. The aim of the group is to understand at the physical chemical level how proteins bind nucleic acids and exploit this knowledge to rationally design new proteins and small molecule drugs that control human regulatory networks or repress viral replication. Members of the group use spectroscopic (NMR), crystallographic, computational and biochemical techniques.

Gene expression is central in biology - The human genome contains only 5 times as many genes as yeast, yet complex networks regulating gene expression multiply our complexity. Different genes are copied into messenger RNA differently and afterwards mRNAs are chemically processed, localized in the cell and translated into proteins differently. These processes multiply the number of distinct proteins coded by our genome, and makes highly evolved tissues, such as the brain, 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. It is estimated that 15% of all human genetic diseases are attributable to errors in mRNA processing.

Proteins that bind 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 viruses such as HIV and Hepatitis C exploit the human gene expression machinery to replicate by studying how viral and human proteins and RNA interact with each other. The group is also investigating the three-dimensional structure of telomerase, an enzyme composed of both RNA and protein components responsible for maintenance of the physical ends of chromosomes. Telomerase is a new target for anticancer therapy because it is selectively activated in >95% of all human cancers.

NMR structure of a peptidomimetic compound bound to HIV TAR RNA

Control of gene expression depends on molecular recogniton 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 new activities to control these processes.

The long-term goal of the research group is to design proteins 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 proteins and small molecule drugs that control gene expression networks. This is the fundamental goal of the Varani research group. Ultimately, we want to be able to rationally design new proteins and synthesize small molecule drugs that control gene expression networks. New designer proteins would provide ideal reagents to dissect gene expression pathways, while small molecule drugs that interfere with nucleic acid metabolism would be of tremendous value in the treatment of infectious disease.

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