History of the Science: Historically, the bioinformatic approach to the development of unknown protein and polypeptide products was to identify specific sequence similarities in extended databases. In contrast, using theoretical and computational approaches from a variety of fields, we look for underlying topological and metric patterns in real number sequences. These sequential patterns or "modes" are obtained from thermodynamically relatable transformations of nucleotide and/or amino acid sequences based on individually quantifiable physical properties. The sequential patterns or "modes" are then used to design receptor targeted L- and D-amino acid "peptide drugs" that are peptidase resistant and orally active.
Patents: In January 2000, the Institute applied for national and international patents, for both its applied computational techniques and its peptide products. On May 6, 2003, the US patent office issued Algorithmic Design of Peptides for Binding and/or Modulation of the Functions of Receptors and/or Other Proteins (pat. no. 6,560,542). In March of 2005, it issued patent no. 6,865,492 on related methods. On June 5, 2007, Cielo Institute was granted patents on 95 specific peptide sequences with protein receptor targets (see US pat no. 7,228,238). Two additional patents are pending.
Discoveries: Using these methods, we have designed novel peptide ligands targeting dopaminergic, M1 muscarinic, glutaminergic, corticotropin and growth factor receptors, with 30% to 50% or greater "hit rates". These ligands have demonstrated both direct and allosteric modulatory properties in a variety of in vitro and in vivo assays. Recent work has indicated that a set of our D2 dopamine receptor targeted allosteric peptides correct attentional defects in an animal model of ADHD.These peptides have been shown to produce significant, long-lasting behavioral changes when given peripherally.
Mandell, A.J. (1984) Non-equilibrium behavior of some brain enzyme and receptor systems. Ann. Rev. Pharm. Toxicol.24: 237-274.
Mandell, A.J. (1985) Primetimes: The distribution of singularities in hydrophobic free energy of proteins. In (M.F. Shlesinger, R. Cawley, A.W. Saeuz and W. Zachary, eds) Perspectives in Nonlinear Dynamics. World Scientific: Singapore. pp. 259-278.
Mandell, A.J. (1987) Polypeptide hormones and receptors: Participants in and products of a two parameter, dissipative, measure-preserving, smooth dynamical system in hydrophobic mass energy. In (H. Degn, A.V. Holden and L.F.Olsen, eds) Chaos in Biological Systems. Plenum:N.Y. pp. 33-48.
Mandell, A.J., Russo, P.V. and Blomgren, B.W. (1987) Complex hydrophobic sequence transformation predicts mutual recognition by polypeptides and proteins. Ann. N.Y. Acad. Sci.504: 88-118. PMID: 2820290
Mandell, A.J. (1988) The source and characteristics of normal modes in molecular biology. In (M. Velarde, ed) Chaos and Order in the Natural Sciences. Springer-Verlag:N.Y. pp. 351-368.
Mandell, A.J. and Selz, K.A. (1992) Critical allosteric brain enzyme kinetics and phenotypic evolutionary processes. In (J. Mittenthal and A. Baskins, eds) Dynamical Systems in Evolutionary Biology. Santa Fe Institute/Addison-Wesley:Reading. pp. 225-240.
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (1997) Mode homologies and their locations in the hydrophobic free energy sequences of peptide ligands and their receptor eigenfunctions. Proc. Natl. Acad. Sci.94: 13576-13581.PMID: 9391068
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (1997) Wavelet transformation of protein hydrophobicity sequences suggests their memberships in structural families. PhysicaA244: 254-262.
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (1997) Hydrophobic free energy eigenfunctions help define continuous wavelet transformations of amino acid sequences of protein families. Proc. Intl. (Fermi) Sch. Phys.CXXXIV: 175-192.
Di Marzio, E.A. and Mandell, A.J. (1997) Phase transition behavior of a linear macromolecule threading a membrane. J. Chem Phys.197:5510-5514.
Mandell, A.J., Owens, M.J., Selz, K.A., Morgan, W.N., Shlesinger, M.F. and Nemeroff, C.G. (1998) Mode matches in hydrophobic free energy eigenfunctions predict (neurotensin, cholescystokinin) peptide-protein interactions. Biopolymers46:89-101. PMID: 9664843
Selz, K.A., Mandell, A.J. and Shlesinger, M.F. (1998) Hydrophobic free energy eigenfunctions of pore, channel and transporter proteins contain beta-burst patterns. Biophys. J.75:2332-2342. PMID: 9788928
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (1998) Transformational homologies in amino acid sequences suggest memberships in protein families. J. Stat. Phys.93:673-697.
Mandell, A.J., Selz, K.A., Shlesinger, M.F. and M.J. Kuhar (1999) Linear and entropic transformations of the hydrophobic free energy sequence help characterize a novel brain protein: CART. In (M.T. Batchelor and L.Wille, eds.) Statistical Physics on the Eve of the Twenty-First Century. World Scientific, NJ, pp. 131-152.
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (2000) A computational approach to the sometime one-dimensional problems of peptide-receptor and chaperone-protein binding. J. Phys. Chem.104(16): 3953-3959.
Mandell, A.J., Selz, K.A. and Shlesinger, M.F. (2000) Protein binding predictions from primary sequence hydrophobicity. J. Mol. Liquids86: 163-171.
Mandell, A.J., Selz, K.A., Owens, M.J., Shlesinger, M.F., Gutman, D.A. and Arcuragi, V. (2001) Hydrophobic mode-targeted, algorithmically designed, peptide ligands as modulators of protein thermodynamic structure and function. In (R. Raffa, ed.) The Thermodynamics of Ligand Receptor Interactions. Wiley, N.Y., pp. 655-700.
Mandell, A.J., Selz, K.A., Owens, M.J., and Shlesinger, M.F. (2003) Broomhead-King hydrophobic modes in receptor-targeted peptide design: How to find modes in a short data sequence. In (S. Bezrukov, ed) Unsolved Problems of Noise and Fluctuations in Physics, Biology and High Technology, 553-559.
Mandell, A.J., Selz, K.A., Owens, M.J., Kinkead, B., Shlesinger, M.F., Gutman, D.A. and Arguragi, V. (2003) Cellular and behavioral effects of D2 dopamine receptor hydrophobic eigenmode-targeted peptide ligands. Neuropsychopharmacology. 28: S98-S107.PMID: 12827150
Selz, K.A., Mandell, A.J., Shlesinger, M.F., Arguragi, V., and Owens, M.J. (2004) Designing Human m1 muscarinic receptor-targeted hydrophobic eigenmode matched peptides as functional modulators. Biophysical J.86:1308-1332.
Kinkead, B., Selz, K.A., Owens, M.J. and Mandell, A.J. (2004) Algorithmically designed D2 targeted, allosteric peptides ameliorate behavioral defects in an animal model of ADHD. Poster presented at the ACNP 2004 annual meeting, Peurto Rico.
Kinkead, B., Selz, K.A., Owens, M.J. and Mandell, A.J. (2006) Algorithmically designed peptides ameliorate behavioral defects in an animal model of ADHD. J. Neurosci. Meth.151:68-81.
Selz, K.A., Samoylova, T.I., Samoylov, A.M., Vodyanoy, V.J. and Mandell, A.J. (2007) Designing allosteric peptide ligands targeting a globular protein. Biopolymers 85(1): 38-59.