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Now showing items 1 - 16 of 4137

  • Site-Selective Synthesis of Insulin Azides and Bioconjugates

    Boga, Sobhana Babu   Krska, Shane W.   Lin, Songnian   Pissarnitski, Dmitri   Yan, Lin   Kekec, Ahmet   Tang, Weijuan   Pierson, Nicholas A.   Strulson, Christopher A.   Streckfuss, Eric   Zhu, Xiaohong   Zhang, Xiaoping   Kelly, Terri   Parish, Craig A.  

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  • Site-Selective Synthesis of Insulin Azides and Bioconjugates

    Boga, Sobhana Babu   Krska, Shane W.   Lin, Songnian   Pissarnitski, Dmitri   Yan, Lin   Kekec, Ahmet   Tang, Weijuan   Pierson, Nicholas A.   Strulson, Christopher A.   Streckfuss, Eric   Zhu, Xiaohong   Zhang, Xiaoping   Kelly, Terri   Parish, Craig A.  

    A synthetic method to access novel azido-insulin analogs directly from recombinant human insulin (RHI) was developed via diazo-transfer chemistry using imidazole-1-sulfonyl azide. Systematic optimization of reaction conditions led to site-selective azidation of amino acids B1-phenylalanine and B29-lysine present in RHI. Subsequently, the azido-insulin analogs were used in azide-alkyne [3 + 2] cycloaddition reactions to synthesize a diverse array of triazole-based RHI bioconjugates that were found to be potent human insulin receptor binders. The utility of this method was further demonstrated by the concise and controlled synthesis of a heterotrisubstituted insulin conjugate.
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  • Cis -> Trans Isomerization of Pro(7) in Oxytocin Regulates Zn2+ Binding

    Fuller, Daniel R.   Glover, Matthew S.   Pierson, Nicholas A.   Kim, DoYong   Russell, David H.   Clemmer, David E.  

    Ion mobility/mass spectrometry techniques are employed to investigate the binding of Zn2+ to the nine-residue peptide hormone oxytocin (OT, Cys(1)-Tyr(2)-Ile(3)-Gln(4)-Asn(5)-Cys(6)-Pro(7)-Leu(8)-Gly(9)-NH2, having a disulfide bond between Cys(1) and Cys(6) residues). Zn2+ binding to OT is known to increase the affinity of OT for its receptor [Pearlmutter, A. F., Soloff, M. S.: Characterization of the metal ion requirement for oxytocin-receptor interaction in rat mammary gland membranes. J. Biol. Chem. 254, 3899-3906 (1979)]. In the absence of Zn2+, we find evidence for two primary OT conformations, which arise because the Cys(6)-Pro(7) peptide bond exists in both the trans- and cis-configurations. Upon addition of Zn2+, we determine binding constants in water of K-A =3D 1.43 +/- 0.24 and 0.42 +/- 0.12 mu M-1, for the trans- and cis-configured populations, respectively. The Zn2+ bound form of OT, having a cross section of Omega =3D 235 (2), has Pro(7) in the trans-configuration, which agrees with a prior report [Wyttenbach, T., Liu, D., Bowers, M. T.: Interactions of the hormone oxytocin with divalent metal ions. J. Am. Chem. Soc. 130, 5993-6000 (2008)], in which it was proposed that Zn2+ binds to the peptide ring and is further coordinated by interaction of the C-terminal, Pro(7)-Leu(8)-Gly(9)-NH2, tail. The present work shows that the cis-configuration of OT isomerizes to the trans-configuration upon binding Zn2+. In this way, the proline residue regulates Zn2+ binding to OT and, hence, is important in receptor binding.
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  • Proline-to-cysteine cyclization for generating conformationally constrained cyclic peptides

    Essman, Jake Z.   Huang, Chunhui   Pierson, Nicholas A.   Pissarnitski, Natalya   Meng, Tao  

    Macrocyclic peptides have received increasing attention throughout the pharmaceutical industry as attractive scaffolds for the development of new therapeutics. Here, we describe the development of a new proline-to-cysteine (PTC) peptide cyclization reaction. Peptide sequences flanked by an N-terminal proline and a C-terminal cysteine were reacted with alpha,alpha'-dibromo-m-xylene to furnish cyclic peptides bearing a tertiary amine embedded within the macrocycle backbone. Macrocyclization proceeded efficiently in solution and on-resin with peptides of different sequence lengths (5-10 amino acids) and amino acid compositions. This approach was also applied for peptide bicyclization. Liquid chromatography mass spectrometry (LC-MS)/MS analysis of a fingerprint ion related to the PTC linkage that was present throughout the substrate scope expedited confirmation of the product cyclic topologies. Conformational studies by variable-temperature NMR revealed PTC macrocycles can adopt a rigid structure and display an intramolecular hydrogen-bonding pattern that differs significantly from their cysteine-to-cysteine linked counterparts, further highlighting the value of this alternative cyclization approach. Due to its compatibility with library-based peptide display and selection technologies, the described approach could offer significant utility in drug discovery campaigns.
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  • Number of Solution States of Bradykinin from Ion Mobility and Mass Spectrometry Measurements

    Pierson, Nicholas A.   Chen, Liuxi   Valentine, Stephen J.   Russell, David H.   Clemmer, David E.  

    Ion mobility and mass spectrometry measurements have been used to examine the populations of different solution structures of the nonapeptide bradykinin. Over the range of solution compositions studied, from 0:100 to 100:0 methanol:water and 0:100 to 90:10 dioxane:water, evidence for 10 independent populations of bradykinin structures in solution is found. In some solutions as many as eight structures may coexist. The solution populations are substantially different than the gas-phase equilibrium distribution of ions, which exhibits only three distinct states. Such a large number of coexisting structures explains the inability of traditional methods of characterization such as nuclear magnetic resonance spectroscopy and crystallography to determine detailed structural features for some regions of this peptide.
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  • Evidence for a Quasi-Equilibrium Distribution of States for Bradykinin [M+3H](3+) Ions in the Gas Phase

    Pierson, Nicholas A.   Valentine, Stephen J.   Clemmer, David E.  

    Multidimensional ion mobility spectrometry coupled with mass spectrometry (IMS-IMS-MS) techniques are used to select and activate six different gas-phase conformations of bradykinin [M + 3H](3+) ions. Drift time distributions as a function of activation voltage show that at low voltages selected structures undergo conformational transitions in what appears to be a pathway dependent fashion. Over a relatively wide range of intermediate activation voltages a distribution of states that is independent of the initial conformation selected for activation (as well as the activation voltage in this intermediate region) is established. This distribution appears to represent an equilibrium distribution of gas-phase structures that is reached prior to the energy required for dissociation. Establishment of a quasi-equilibrium prior to dissociation results in identical dissociation patterns for different selected conformations. A discussion of the transition from solution-like to gas-phase structures is provided.
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  • From Solution to the Gas Phase:Stepwise Dehydration and Kinetic Trapping of Substance P Reveals the Origin of Peptide Conformations

    Silveira, Joshua A.   Fort, Kyle L.   Kim, DoYong   Servage, Kelly A.   Pierson, Nicholas A.   Clemmer, David E.   Russell, David H.  

    Past experimental results and molecular dynamics simulations provide evidence that, under some conditions, electrospray ionization (ESI) of biomolecules produces ions that retain elements of solution phase structures. However, there is a dearth of information regarding the question raised by Breuker and McLafferty, "for how long, under what conditions, and to what extent, can solution structure be retained without solvent?" (Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 18145). Here, we use cryogenic ion mobility-mass spectrometry to experimentally probe the structural evolution of the undecapeptide substance P (SP) during the final stages of ESI. The results reveal that anhydrous SP conformers originate from evaporation of cluster ions, specifically, [SP + 2H](2+) (H2O)(n) (n =3D 0 to similar to 50) and [SP + 3H](3+) (H2O) (n =3D 0 to similar to 30), and that major structural changes do not occur during the evaporative process. In the case of [SP + 3H](3+), the results demonstrate that a compact dehydrated conformer population can be kinetically trapped on the time scale of several milliseconds, even when an extended gas phase conformation is energetically favorable.
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  • Cis\r –\r Trans\r Isomerizations of Proline Residues Are Key to Bradykinin Conformations

    Pierson, Nicholas A.   Chen, Liuxi   Russell, David H.   Clemmer, David E.  

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  • Once a physicist: Alan Pierson

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  • Kidney transplantation in a child with Pierson syndrome.

    Guler, Sanem   Cimen, Sertac   Acott, Phillip   Whelan, Kathy   Molinari, Michele  

    Congenital nephrotic syndrome is commonly associated with mutations in genes that encode podocyte and slit diaphragm proteins or the structural and regulatory proteins of the GBM. These mutations lead to the formation of dysfunctional proteins, which account for the resistance of the renal manifestations to conventional treatment methods. Consequently, patients become renal replacement therapy dependent. Mutation of the LAMB2 gene is associated with Pierson syndrome, which is an autosomal recessive disorder characterized by congenital nephrotic syndrome and ocular abnormalities. In this report, a 2-year-old male patient who was diagnosed with Pierson syndrome is presented. He had bilateral microcoria and developmental delay in addition to nephrotic syndrome. His renal function deteriorated rapidly, and he underwent a deceased donor kidney transplantation. He showed dramatic improvement after kidney transplantation; in addition to having good renal function, he started to catch up to his peers in terms of growth. Pierson syndrome should be considered during the diagnostic investigations of children with renal manifestations and ocular abnormalities. Children with Pierson syndrome must be evaluated in terms of kidney transplantation as soon as they are diagnosed. =C2=A9 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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  • Kidney transplantation in a child with Pierson syndrome

    Guler, Sanem   Cimen, Sertac   Acott, Phillip   Whelan, Kathy   Molinari, Michele  

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  • Charon A. Pierson, PhD, GNP, FAAN, FAANP In Memorium

    Pierson, Charon A.  

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  • A Tribute to Nicholas Certo

    Wehman   Paul  

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  • Pierson Syndrome - A Rare Cause of Congenital Nephrotic Syndrome

    Lionel, Arul Premanand   Joseph, Leni Kumar   Simon, Anna  

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  • A Conversation with Nicholas Proudfoot

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  • Nicholas A. Vick, MD (1939-2014)

    McMahon, J. P.   Groothuis, D. R.   Homer, D.   Maraganore, D. M.  

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