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Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl 下载免费PDF全文
Zoltan Dekan Dr. Mehdi Mobli Dr. Michael W. Pennington Dr. Eileen Fung Dr. Elizabeta Nemeth Prof. Paul F. Alewood 《Angewandte Chemie (International ed. in English)》2014,53(11):2931-2934
A safety‐catch cysteine protecting group, S‐4,4′‐dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine‐rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high‐resolution NMR structure under more physiologically relevant conditions than previously. Conversely, hepcidin synthesized with the formerly assigned vicinal disulfide‐bond connectivity displayed significant conformational heterogeneity under similar conditions. The two synthetic forms of human hepcidin induced ferroportin internalization with apparent EC50 values of 2.0 (native fold, 1 ) and 4.4 nM (non‐native fold, 2 ), with 2 undergoing isomerization to 1 in the presence of ferroportin expressing cells. 相似文献
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Boned R van Gunsteren WF Daura X 《Chemistry (Weinheim an der Bergstrasse, Germany)》2008,14(16):5039-5046
The temperature dependence of thermodynamic quantities, such as heat capacity, entropy and free enthalpy, may be obtained by using well-known equations that relate these quantities to the enthalpy of the molecular system of interest at a range of temperatures. In turn, the enthalpy of a molecular system can be estimated from molecular dynamics simulations of an appropriate model. To demonstrate this, we have investigated the temperature dependence of the enthalpy, heat capacity, entropy and free enthalpy of a system that consists of a beta-heptapeptide in methanol and have used the statistical mechanics relationships to describe the thermodynamics of the folding/unfolding equilibrium of the peptide. The results illustrate the power of current molecular simulation force fields and techniques in establishing the link between thermodynamic quantities and conformational distributions. 相似文献
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Dr. Nitin A. Patil Dr. John A. Karas Prof. Dr. John D. Wade Dr. Mohammed Akhter Hossain Dr. Julien Tailhades 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(36):8599-8603
Structure–activity relationship studies are a highly time-consuming aspect of peptide-based drug development, particularly in the assembly of disulfide-rich peptides, which often requires multiple synthetic steps and purifications. Therefore, it is vital to develop rapid and efficient chemical methods to readily access the desired peptides. We have developed a photolysis-mediated “one-pot” strategy for regioselective disulfide bond formation. The new pairing system utilises two ortho-nitroveratryl protected cysteines to generate two disulfide bridges in less than one hour in good yield. This strategy was applied to the synthesis of complex disulfide-rich peptides such as Rho-conotoxin ρ-TIA and native human insulin. 相似文献
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Bayó-Puxan N Fernández A Tulla-Puche J Riego E Cuevas C Alvarez M Albericio F 《Chemistry (Weinheim an der Bergstrasse, Germany)》2006,12(35):9001-9009
Thiocoraline is a potent antitumor agent isolated from the marine organism Micromonospora sp. This symmetric bicyclic depsipeptide binds the minor groove of DNA. Here we report two solid-phase strategies for the syntheses of azathiocoraline and its analogues. The thioester linkage was replaced by an amide bond to improve the compound's pharmacokinetic properties. The first strategy is based on a convergent (4+4) approach, whilst the second is a stepwise synthesis, cyclizations in both approaches occurring on the solid support. These two strategies were designed to overcome problems caused by the presence of consecutive noncommercial N-methyl amino acids, to avoid epimerization during cyclization and/or fragment condensation, and to form the disulfide bridge under solid-phase conditions. The heterocyclic moiety was added in the last step of the synthesis to assist the preparation of libraries of new compounds with potential therapeutic applications. 相似文献
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Autocrine‐Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries 下载免费PDF全文
Dr. Hongkai Zhang Dr. Mingjuan Du Dr. Jia Xie Xiao Liu Jingying Sun Dr. Wei Wang Xiu Xin Prof. Lourival D. Possani Dr. Kyungmoo Yea Prof. Richard A. Lerner 《Angewandte Chemie (International ed. in English)》2016,55(32):9306-9310
Animal venoms represent a rich source of pharmacologically active peptides that interact with ion channels. However, a challenge to discovering drugs remains because of the slow pace at which venom peptides are discovered and refined. An efficient autocrine‐based high‐throughput selection system was developed to discover and refine venom peptides that target ion channels. The utility of this system was demonstrated by the discovery of novel Kv1.3 channel blockers from a natural venom peptide library that was formatted for autocrine‐based selection. We also engineered a Kv1.3 blocker peptide (ShK) derived from sea anemone to generate a subtype‐selective Kv1.3 blocker with a long half‐life in vivo. 相似文献
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Cover Picture: Autocrine‐Based Selection of Drugs That Target Ion Channels from Combinatorial Venom Peptide Libraries (Angew. Chem. Int. Ed. 32/2016) 下载免费PDF全文
Dr. Hongkai Zhang Dr. Mingjuan Du Dr. Jia Xie Xiao Liu Jingying Sun Dr. Wei Wang Xiu Xin Prof. Lourival D. Possani Dr. Kyungmoo Yea Prof. Richard A. Lerner 《Angewandte Chemie (International ed. in English)》2016,55(32):9099-9099
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Two acceptor containing polyimides PDI and NDI carrying pyromellitic diimide units and 1,4,5,8-naphthalene tetracarboxy diimide
units, respectively, along with hexa(oxyethylene) (EO6) segments as linkers, were prepared from the corresponding dianhydrides
and diamines. These polyimides were made to fold by interaction with specifically designed folding agents containing a dialkoxynaphtha-lene
(DAN) donor linked to a carboxylic acid group. The alkali-metal counter-ion of the donor carboxylic acid upon complexation
with the EO6 segment brings the DAN unit in the right location to induce a charge-transfer complex formation with acceptor
units in the polymer backbone. This two-point interaction between the folding agent and the polymer backbone leads to a folding
of the polymer chain, which was readily monitored by NMR titrations. The effect of various parameters, such as structures
of the folding agent and polymer, and the solvent composition, on the folding propensities of the polymer was studied. 相似文献
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《Journal of computational chemistry》2017,38(11):790-797
The folding processes of mini‐proteins (FSD‐EY/FBPWW28 domain) were computationally investigated by an enhanced conformational sampling method. Through the analyses of trajectories, these mini‐proteins had multiple folding pathways different from a simple two‐state folding, and the multiple folding processes were initiated by partial formations of secondary structures. These findings can be used to understand the folding of large proteins, that is, which secondary structures are partially folded in the early process, and how the remaining parts are sequentially folded. It is found that FSD‐EY (α/β topology) folds by a simple diffusion‐collision mechanism, while the folding process of the FBPWW28 domain (all‐β topology) requires a modification of the diffusion‐collision theory to adequately treat the coil‐sheet transition for the β sheet formation. © 2017 Wiley Periodicals, Inc. 相似文献
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Starting with the Levinthal paradox, a brief introduction to the protein folding problem is presented. The existing theories
of protein folding, including the folding funnel scenario, are discussed. After briefly discussing different simulation studies
of model proteins, we discuss our recent work on the dynamics of folding of the model HP-36 (the chicken villin headpiece)
protein by using a simplified hydropathy scale. Special attention has been paid to the statics and dynamics of contact formation
among the hydrophobic residues. The results obtained from this simple model appear to be surprisingly similar to several features
observed in the folding of real proteins. The account concludes with a discussion of future problems.
Received: 28 April 2002 / Accepted: 11 August 2002 / Published online: 13 November 2002
Correspondence to: B. Bagchi e-mail: bbagchi@sscu.iisc.ernet.in
Acknowledgements. We thank Samir Pal and Arnab Mukherjee for many discussions and Arun Yethiraj for helpful suggestions. The financial support
from DST, India, is gratefully acknowledged. G. S. thanks CSIR for a research fellowship. 相似文献