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Animals↗
Biomedical subjects
Michael F Shlesinger
Publications and source records attributed to Michael F Shlesinger.
Designing human m1 muscarinic receptor-targeted hydrophobic eigenmode matched peptides as functional modulators.
A new proprietary de novo peptide design technique generated ten 15-residue peptides targeting and containing the leading nontransmembrane hydrophobic autocorrelation wavelengths, "modes", of the human m(1) muscarinic cholinergic receptor, m(1)AChR. These modes were also shared by the m(4)AChR subtype (but not the m(2), m(3), or m(5) subtypes) and the three-finger snake toxins that pseudoirreversibly bind m(1)AChR. The linear decomposition of the hydrophobically transformed m(1)AChR amino acid sequence yielded ordered eigenvectors of orthogonal hydrophobic variational patterns. The weighted sum of two eigenvectors formed the peptide design template. Amino acids were iteratively assigned to template positions randomly, within hydrophobic groups. One peptide demonstrated significant functional indirect agonist activity, and five produced significant positive allosteric modulation of atropine-reversible, direct-agonist-induced cellular activation in stably m(1)AChR-transfected Chinese hamster ovary cells, reflected in integrated extracellular acidification responses. The peptide positive allosteric ligands produced left-shifts and peptide concentration-response augmentation in integrated extracellular acidification response asymptotic sigmoidal functions and concentration-response behavior in Hill number indices of positive cooperativity. Peptide mode specificity was suggested by negative crossover experiments with human m(2)ACh and D(2) dopamine receptors. Morlet wavelet transformation of the leading eigenvector-derived, m(1)AChR eigenfunctions locates seven hydrophobic transmembrane segments and suggests possible extracellular loop locations for the peptide-receptor mode-matched, modulatory hydrophobic aggregation sites.
Algorithms↗
Cellular and behavioral effects of D2 dopamine receptor hydrophobic eigenmode-targeted peptide ligands.
Patterns in G-protein-coupled receptors' hydrophobically transformed amino-acid sequences can be computationally characterized as hierarchies of autocorrelation waves, "hydrophobic eigenmodes", using autocovariance matrix decomposition and all poles power spectral and wavelet transformations. L- or D-amino acid (retro-inverso) 12-18 residue peptides targeting these modes can be designed using eigenvector templates derived from these computations. In all, 12 human long-form D(2) dopamine receptor eigenmode-targeted 15 mer peptides were designed, synthesized, and shown to modulate and/or indirectly activate the extracellular acidification response, EAR, in stably receptor-transfected CHO and LtK cells, with an 83% hit rate. Representative L- and D-amino-acid retro-inverso peptides injected bilaterally in the nucleus accumbens demonstrated changes in rat exploratory behavior and prepulse inhibition similar to those observed following parenteral amphetamine. In contrast with geometric models used for ligand design, such as pharmacophores, the hydrophobic eigenmode approach to lead modulatory peptide design targets hydrophobic eigenmode-bearing subsequences, including those not visible from X-ray and NMR studies such as extracellular segments and loops.
Amino Acid Sequence↗