3rd year Postdoctoral Fulbright fellow at Pam Silver's lab (http://silver.med.harvard.edu/.)
B.S (1995-2000): I got my B.S. in chemistry at the University of Buenos Aires (School of Exact and Natural Science), in Argentina. In 1997 I started to work as an undergraduate researcher in “Asymmetric electrosynthesis” under the supervision of Prof. Fabio Doctorovich at the Inorganic, Physicochemical and Analytical Department. In 1998 I joined Prof. Oscar Varela's group at the Organic Chemistry Department where I worked on “Asymmetric synthesis, using abundant natural products as chirals scaffolds” until I finished my B.S/M.S. in 2000.
Ph.D (2001-2004): Looking for an experience abroad to do my Ph.D. I moved to Barcelona, Spain where I joined Prof. Albericio's group at the Biomedical Research Institute, Barcelona Scientific Park – University of Barcelona. Under F. Albericio and M. Alvarez's supervision I started to work in solid-phase synthesis of natural products and heterocyclic compounds where my major success was to achieve the first Solid-Phase Total Synthesis of the Pentacyclic System Lamellarins U and L.
1) Quantitatively Designed Protein Therapeutics
Many protein drugs are naturally occurring proteins that have been designed by evolution to act locally, but must be administered systemically. Examples include interferon alpha (IFNα) and tumor necrosis factor (TNF). Serious side effects often result from the drug’s action on non-target cells. The side effects may limit the dose that can be given, or prevent a drug from being used at all. My research is focused on the development of a new class of protein drugs (chimeric activators) that are designed based on principles of quantitative systems biology. “Chimeric Activators” proteins consist of a Targeting Element and an Activity Element. The targeting element binds to a molecule on the surface of a target cell. The activating element has the desired biological activity. However, the activating element must be mutated so that its intrinsic binding to its receptor is weak, and binding is driven by the Targeting Element.
2) Functional nucleus-cytoplasmic shuttling analysis by cell-based-screening of miRNAs:
Human immunodeficiency virus type 1 (HIV-1) Rev protein is essential for viral replication. Rev functions to export unspliced or singly spliced HIV precursor mRNAs from the nucleus. This nuclear transit requires two signal sequences: a nuclear localization signal (NLS) that overlaps the RNA-binding domain, and an export signal (NES) that enables Rev to shuttle. The Rev-type export sequences function by directly binding to a nuclear export receptor, named CRM1/exportin. In order to understand more about the mechanism of the Rev mediated transport and general transport factors between the nucleus and the cytoplasm, we engineered a cell line that allows us to study this shuttling process by modulating the expression of different proteins. Our approach uses HTS (high throughput screening) and high throughput microscopy by using miRNAs, a human kinase library and also small molecules as nuclear transport modulators.
1) P. Cironi, IA. Swinburne, PA. Silver, "Enhancement of cell-type specificity by quantitative modulation of a chimeric ligand". J. Biol chem., 2008, 283, 8469-8476.
2) Z. Zhou*, P. Cironi*, AJ. Lin*, Y. Xu, S. Hrvatin, DE. Golan, PA. Silver, CT. Walsh, J. Yin, “Genetically encoded short peptide tags for orthogonal protein labeling by Sfp and AcpS phosphopantetheinyl transferases”. ACS Chemical Biology, 2007, 2, 337-346. (* These authors contribute equally)
3) N. Roque-Rosell, P. Cironi, X. Solans, F. Albericio, M. Alvarez. “1-Hydroxy-6,7-dimethoxy-8-nitro-1,2,3,4-tetrahydroisoquinoline”. Acta Crystallographica, Section E: Structure Reports Online 2006, 62, 2285-2287.
4) P. Cironi, J. Tulla-Puche, G. Barany, F. Albericio, M. Álvarez. “Solid-phase Syntheses of Furopyridine and Furoquinoline Systems”. Org. Lett., 2004, 6, 1405-1408.
5) P. Cironi, F. Albericio, M. Álvarez. “Solid-Phase Synthesis of 4H-2-(3-Hydroxy-4-methoxyphenyl)naphtho[1,2-b]pyran-1-one”. Tetrahedron Lett. 2004, 45, 7311-7314.
6) P. Cironi, C. Cuevas, F. Albericio, M. Álvarez. “Gaining Diversity in Solid-Phase Synthesis by Modulation of Cleavage Conditions from Hydroxymethyl-based Supports. Application to Lamellarin Synthesis”. Tetrahedron, 2004, 60, 8669-8675.
7) D. Fernández, A. Ahaidar, G. Danelón, P. Cironi, M. Marfil, O. Pérez, C. Cuevas, F. Albericio, J. A. Joule, M. Álvarez. “Synthesis of Polyheterocyclic Nitrogen-Containing Marine Natural Products”. Monatshefte fur chemie, 2004, 135, 615-627.
8) P. Cironi, M. Álvarez, F. Albericio. “A Combination of different spectroscopy techniques to monitor “in situ” solid-phase synthesis of organic molecules”. QSAR & Comb. Sci., 2004, 23, 61-68.
9) P. Cironi, M. Álvarez, F. Albericio. “1H NMR Spectroscopy with Internal and External Standards for the Quantification of Libraries”. Molecular Diversity, 2003, 6, 165-168.
10) P. Cironi , I. Manzanares, F. Albericio, M. Álvarez. “Solid-Phase Total Synthesis of the Pentacyclic System Lamellarins U and L”. Org. Lett., 2003, 5, 2959-2962.
11) P. Cironi & O. Varela. “Synthesis of 3,4-di-O-benzyl-1-O-methyl-L-galactitol a key precursor of the C33-C37 fragment of calyculins”. J Braz. Chem. Soc., 2001, 12, 667-672.
12) PA. Silver, P. Cironi. “Chimeric activators: Quantitatively design proteins therapeutics”. PCT. Int. Appl. (2008), WO 2008124086 A2.
13) F. Albericio, M. Álvarez, P. Cironi, C. Cuevas, A. Francesch, M. Marfil. “Solid phase synthesis of antitumoral compounds”. PCT Int. Appl. WO 2004/073598 A2. Publication day: 2 September 2004.
14) P. Cironi, F. Albericio, M. Álvarez. “Lamellarins: Isolation, activity and synthesis”. Progress in Heterocyclic Chemistry, 2004, Vol. 16, Ch. 1 p.1-26 Ed G. W. Gribble, J. A. Joule, Pergamon, Oxford, U.K.
15) P. Cironi, M. Álvarez, F. Albericio. “Solid-phase chemistry in the total synthesis of non-peptidic natural products”. Mini-reviews in Medicinal Chemistry, 2006, 6, 15.
For further information you can reach me at my new address:
Pablo Cironi Ph D.