个人简介

La Riccia Foundation Fellow, 1987-1989 Founder, Ribotargets, 1997; now Vernalis VER on London Stock Exchange; VNLS on Nasdaq Visiting Professor, Universita’ di Roma, 2000 Gilead Lecture, NACOM V, Sheffield, 2001 > 200 invited lectures and presentations

研究领域

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)

近期论文

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H. Walbott, R. Machado-Pinilla, D. Liger, M. Blaud, S. Réty4, P. N. Grozdanov, K. Godin, H. van Tilbeurgh, G. Varani, U. T. Meier, N. Leulliot The H/ACA assembly factor Shq1 functions as an RNA mimic Genes Develop (2011) Y. Chen and G. Varani Finding the missing code of RNA recognition by PUF proteins Chem. & Biol. 18 (2011) W. Huang, G.Varani and G. D. Drobny Interactions of Tat Protein Side Chains with TAR RNA Defined with 13C/15N{31P/19F} REDOR NMR J. B. NMR (2011) M. F. Bardaro and G. Varani Examining the Relationship between RNA Function and Motion using NMR RNA Wires (2011) Y. Niu, A. J. Jones, H. Wu, G. Varani and J. Cai γ-AApeptides bind to RNA by mimicking RNA-binding proteins Organic and Biomolecular Chemistry (2011) R. Stacy, D. W. Begley, I. Phan, B. L. Staker, W. C. Van Voorhis, G. Varani, G. W. Buchko, L. J. Stewart and P. J. Myler Structural genomics of infectious disease drug targets: the SSGCID (2011) R. P Barnwal and G. Varani Double stranded RNA and end-recognition domains in Encyclopedia of Biophysics (2011) I. H. Norville, K. O’Shea, M. Sarkar-Tyson, S. Zheng, R. W. Titball, G. Varani and N. J. Harmer The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development Biochem J. 437 413-422 (2011) 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) A. Davidson, D. W Begley, C. Lau and G. Varani A small molecule probe induces a conformation in HIV TAR RNA capable of binding drug-like fragments J. Mol Biol. 410 984-996 (2011) A. Davidson, K. Patora-Komisarska, J. A. Robinson, G. Varani Essential structural requirements for specific recognition of HIV TAR RNA by peptide mimetics of Tat protein Nucleic Acids Res. 39 248-256 (2011) W. Huang, G.Varani and G. D. Drobny 13C-19F Intermolecular REDOR NMR Study of the Interaction of TAR RNA with Tat Peptides J. Am. Chem. Soc. 132 17643-5 (2010) P. Emani, G. L. Olsen, D. C. Echodu, G. Varani and G. D. Drobny A slow exchange theory of conformational capture in RNA J. Phys. Chem. B 114 15991-6002 (2010) T. C. Leeper, X. Qu, C. Lu, C. Moore and G. Varani Recognition of yeast mRNA 3’-end processing signals by Hrp1 and Rna15 proteins J. Mol. Biol. 401 334-349 (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) D. W. Begley, S. Zheng, D. Clem amd G. VaraniFragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping Chem Bio. And Drug Des. 76 218-233 (2010) 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) G. L. Olsen, M. F. Bardaro, D. C. Echodu, G. P. Drobny and G. Varani Atomic motions of RNA in space and time J. Am. Chem. Soc. 132 303-308 (2010) Y. Liu, E. Peacey, J. Dickson, C. P. Donahue, S. Zheng, G. Varani and M. S. Wolfe Mitoxantrone Analogues as Ligands for a Stem-Loop Structure of Tau Pre-mRNA 52 6523-6526 J. Med. Chem. (2009) D. W. Begley and G. Varani Locking our Viral Replication Nature Chem Biol. 5 782-783 (2009) P. J. Myler, R. Stacy, L. Stewart, B. Staker, W. C. Van Voorhis, G. Varani, G. Buchko The Seattle structural genomics center for infectious diseases (SSGCID) Infect Disord Drug Targets 9 493-506(2009)