[ Research Interests ] [ Representative Publications ]

Ernesto Freire Professor Department of Biology B.S. University Cayetano Heredia Medical School M.S. University Cayetano Heredia Medical School Ph.D. University of Virginia

Department of Biology Johns Hopkins University 3400 North Charles Street Baltimore, MD 21218-2685 U.S.A. Office Telephone: Lab Telephone: Department Fax: Email: 410.516.7743 410.516.7742 410.516.5213 ef@jhu.edu Office- Mudd 114 Lab- Mudd 106

Research Interests The ultimate goal of biomedical research is to cure disease. Fundamental research in this laboratory has resulted in the development of a thermodynamic platform for drug discovery and optimization. This platform is permanently improved and simultaneously applied to the discovery and optimization of novel drugs against important diseases for which no successful therapies are available. HIV/-1 Protease Inhibitors. HIV/AIDS Plasmepsin inhibitors. Malaria HCV Protease inhibitors. Hepatitiis C. Coronavirus 3CL-pro Protease Inhibitors. SARS and other viral infections. HIV-1 gp120 inhibitors. HIV/AIDS HIV-1 Nef inhibitors. HIV/AIDS   Representative Publications Cremades, N., Velazquez-Campoy, A., Freire, E. and Sancho, J. 2008. The Flavodoxin from Helicobacter pylori: Structural Determinants of Thermostability and FMN Cofactor Binding. Biochemistry. 47:627-639. Muzammil, S., Armstrong, A.A., Kang, L.W., Jakalian, A., Bonneau, P.R., Schmelmer, V., Amzel L.M., and Freire, E. 2007. Unique Thermodynamic Response of Tipranavir to HIV-1 Protease Drug Resistance Mutations J. Virology. 81:5144-5154. Hidaka, K., Kimura, T., Tsuchiya, Y., Kamiya, M., Ruben, A.J., Freire, E., Hayashi, Y., and Kiso, Y. 2007. Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II. Bioorg. Medicinal Chem. Letters. 17:3048-3052. Lafont, V., Armstrong, A.A., Ohtaka, H., Kiso, Y., Amzel, M. and Freire, E. 2007. Compensating Enthalpic and Entropic Changes Hinder Binding Affinity Optimization. Chem. Biol. Drug. Design. 69:413-422. Freire, E. A new era for microcalorimetry in drug development 2007. European Pharmaceutical Review 5:73-78. Schon, A. and Freire, E. Strategies for targeting HIV-1 envelope glycoprotein gp120 in the development of new antivirals 2007. Future Medicine 1:223-229. Ruben, A.J, and Freire, E.  The Plasmepsin Family as Antimalarial Drug Targets.  In Proteases as Drug Targets:  Aspartic Acid Proteases, J. Vacca, Ed. Wiley-VCH Verlag GmbH & Co. KGaA. (In Press). Barrila, J., Bacha, U., and Freire, E. 2006. Long-Range Cooperative Interactions Modulate Dimerization in SARS 3CLpro. Thermodynamics of Binding of a Low-Molecular-Weight CD4 Mimetic to HIV-1 gp120. Biochemistry. 45:14908-14916. Velazquez-Campoy, A. and Freire, E. 2006. Isothermal Titration Calorimetry to Determine Association Constants for High Affinity Ligands Nature Protocols 1 186-191. Cremades, N., Sancho, J., and Freire, E. 2006. The native-state ensemble of proteins provides clues for folding, misfolding and function. Trends Biochem Sci.31(9):494-6. Freire, E. 2006. Overcoming HIV-1 Resistance to Protease Inhibitors, Drug Discovery Reviews, 3 281-286 Schön, A., Madani, N., Klein, J.C., Hubicki, A., Ng, D., Yang, K., Smith III, A.B, Sodroski, J. and Freire, F. 2006. Binding Thermodynamics of a Small-Molecular-Weight CD4 Mimetic to HIV-1 gp120, Biochemistry 45 10973-10980 Sydnes, M.O., Hayashi, Y., Sharma, Y.K., Hamada, T., Bacha, U., Barrila, J., Freire, E., and Kiso, Y. 2006. Synthesis of Glutamic Acid and Glutamine Peptides Possessing a Trifluoromethyl Ketone Group as SARS-CoV 3CL Protease Inhibitors, Tetrahedron 62 8601-8609. Groesch, T.D. and Freire, E. 2006. Characterization of intramolecular interactions of HIV-1 accessory protein Nef by differential scanning calorimetry. Biophys Chem. Aguilar, R.C., Longhi, S.A., Shaw, J.D., Yeh, L.Y., Kim, S., Schon, A., Freire, E., Hsu, A.,McCormick, W.K., Watson, H.A., and Wendland, B. 2006. Epsin Nterminal homology domains perform an essential function regulating Cdc42 through binding Cdc42 GTPase-activating proteins. Proc Natl Acad Sci U S A. 103:4116-21. Ruben, A. J., Kiso, Y. and Freire, E. 2006. Overcoming Roadblocks in Lead Optimization:  A Thermodynamic Perspective. Chemical Biology & Drug Design  67 2-4 Ohtaka, H. and Freire, E. Adaptive Inhibitors of the HIV-1 Protease. 2005. Progress in Biophysics and Mol. Bio. 88 193-208. Velásquez-Campoy, A. and Freire, E. 2005. ITC in the post-genomic era...?Priceless, Biophys Chem.  115 115-24 Freire, E. 2005. Antibióticos ineficaces? La Vanguardia, Cataluña, Spain October 9, 2005. Vega, S., Kang, L. W., Velásquez-Campoy, Kiso, Y., Amzel, L. M. and Freire, E. Structural and Thermodynamic Escape Mechanism from a Drug Resistant Mutation of the HIV-1 Protease Proteins 55 594-602. Freire, E. 2005. Isothermal Titration Calorimetry:  Controlling binding forces in lead optimization Drug Discovery Today 1 295-299. Pancera, M., Lebowitz, J., Schön, A., Zhu, P., Zhou, T., Freire, E., Kwong, P., Roux, K.H., Sodroski, J. and Wyatt R. 2005. Soluble Mimetics of HIV-1 Viral Spikes Produced by Replacement of the Native Trimerization Domain with a Heterologous Trimerization Motif: Characterization and Ligand Binding Analysis. 79 9954-9969. Freire, E. 2005. A Thermodynamic Guide to Affinity Optimization of Drug Candidates, Proteomics and Protein-Protein Interactions: Biology, Chemistry, Bioinformatics and Drug Design. 291-307. Carbonell, T. and Freire, E. 2005. The Binding Thermodynamics of Statins to HMG-CoA Reductase.  Biochemistry 44 11741-11748. Murali, R., Cheng, X., Berezov, A., Du, X., Schon, A. Freire, E., Xu, X., Chen, Y. H., and Greene, M. I. 2005. Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107 Proc. Natl. Acad. Sci. USA 102 10970-10975.

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