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Now showing items 1 - 16 of 16

  • An expeditious synthetic route to proteomimetic foldamers

    Karekar, Vaibhav V.   Bhoge, Bapurao A.   Saraogi, Ishu  

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  • A Small Molecule Inhibitor Prevents Insulin Fibrillogenesis and Preserves Activity

    Das, Anirban   Gangarde, Yogesh M.   Tomar, Viniti   Shinde, Omkar   Upadhyay, Tulsi   Alam, Sarfaraz   Ghosh, Sudipta   Chaudhary, Varun   Saraogi, Ishu  

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  • Design and Synthesis of Oligoamide-Based Double -Helix Mimetics

    Kulikov, Oleg V.   Thompson, Sam   Xu, Hai   Incarvito, Christopher D.   Scott, Richard T. W.   Saraogi, Ishu   Nevola, Laura   Hamilton, Andrew D.  

    An extensive series of bis-oligobenzamides and bis-oligopyridylamides have been efficiently prepared and studied by X-ray analysis and computational methods. A modular synthesis led to double -helix mimics bearing between two and ten branched side-chains. The inter-helix angle and distance can be tuned by varying the length and rigidity of the spacer, thereby reproducing the recognition domains of a range of super-secondary structures.
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  • Peptide nucleic acid mediated inhibition of the bacterial signal recognition particle

    Ghosh, Sudipta   Saini, Snehlata   Saraogi, Ishu  

    We have identified the bacterial signal recognition particle (SRP) as a novel antibacterial target. As a proof of principle, we used an antisense peptide nucleic acid to target a key SRP RNA. The PNA molecules showed efficient inhibition of SRP function and bacterial cell growth, thereby validating our hypothesis.
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  • A tale of two GTPases in cotranslational protein targeting

    Saraogi, Ishu   Akopian, David  

    Guanosine triphosphatases (GTPases) comprise a superfamily of proteins that provide molecular switches to regulate numerous cellular processes. The "GTPase switch'' paradigm, in which a GTPase acts as a bimodal switch that is turned "on'' and "off'' by external regulatory factors, has been used to interpret the regulatory mechanism of many GTPases. Recent work on a pair of GTPases in the signal recognition particle (SRP) pathway has revealed a distinct mode of GTPase regulation. Instead of the classical GTPase switch, the two GTPases in the SRP and SRP receptor undergo a series of conformational changes during their dimerization and reciprocal activation. Each conformational rearrangement provides a point at which these GTPases can communicate with and respond to their upstream and downstream biological cues, thus ensuring the spatial and temporal precision of all the molecular events in the SRP pathway. We suggest that the SRP and SRP receptor represent an emerging class of "multistate'' regulatory GTPases uniquely suited to provide exquisite control over complex cellular pathways that require multiple molecular events to occur in a highly coordinated fashion.
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  • Site-Specific Fluorescent Labeling of Nascent Proteins on the Translating Ribosome

    Saraogi, Ishu   Zhang, Dawei   Chandrasekaran, Sandhya   Shan, Shu-ou  

    As newly synthesized proteins emerge from the ribosome, they interact with a variety of cotranslational cellular machineries that facilitate their proper folding, maturation, and localization. These interactions are essential for proper function of the cell, and the ability to study these events is crucial to understanding cellular protein biogenesis. To this end, we have developed a highly efficient method to generate ribosome nascent chain complexes (RNCs) site-specifically labeled with a fluorescent dye on the nascent polypeptide. The fluorescent RNC provides real-time, quantitative information on its cotranslational interaction with the signal recognition particle and will be a valuable tool in elucidating the role of the translating ribosome in numerous biochemical pathways.
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  • Recent advances in the development of aryl-based foldamers

    Saraogi, Ishu   Hamilton, Andrew D.  

    In recent years, significant effort has gone into making synthetic oligomers that can attain well-defined conformations analogous to the folding of biomolecules. The diversity of the structural building blocks ranges from peptidic and other aliphatic repeat units to aromatic ones, which do not have a natural counterpart. In this critical review, we will focus on the developments in aromatic foldamers in the last two years and their potential applications. This review will be of interest to people working on the structural and functional mimicry of biomolecules and will, we hope, stimulate further research into novel applications (149 references).
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  • Controlling Curvature in a Family of Oligoamide alpha-Helix Mimetics

    Saraogi, Ishu   Incarvito, Christopher D.   Hamilton, Andrew D.  

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  • alpha-Helix mimetics as inhibitors of protein-protein interactions

    Saraogi, Ishu   Hamilton, Andrew D.  

    The inhibition of protein-protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the a-helix; these residues frequently play a key role in mediating protein-protein interactions. The first-generation terphenyl scaffold, with a 3,2',2"-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the BCI-X(L)-Bak and the pS3-hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.
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  • α-Helix mimetics as inhibitors of protein–protein interactions

    Saraogi, Ishu   Hamilton, Andrew?D.  

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  • A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes.

    Hebda, James A   Saraogi, Ishu   Magzoub, Mazin   Hamilton, Andrew D   Miranker, Andrew D  

    Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are on pathway to fiber formation. IAPP is not normally amyloidogenic as its cosecreted partner, insulin, prevents self-assembly. Here, we show that IS5 inhibition is synergistic with insulin. IS5 therefore represents a new approach to amyloid inhibition as the target is an assembly intermediate that may additionally restore functional IAPP expression.
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  • Molecular Mechanism of Co-translational Protein Targeting by the Signal Recognition Particle

    Saraogi, Ishu  

    The signal recognition particle (SRP) is a key component of the cellular machinery that couples the ongoing synthesis of proteins to their proper localization, and has often served as a paradigm for understanding the molecular basis of protein localization within the cell. The SRP pathway exemplifies several key molecular events required for protein targeting to cellular membranes: the specific recognition of signal sequences on cargo proteins, the efficient delivery of cargo to the target membrane, the productive unloading of cargo to the translocation machinery and the precise spatial and temporal coordination of these molecular events. Here we highlight recent advances in our understanding of the molecular mechanisms underlying this pathway, and discuss new questions raised by these findings.
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  • Regulation of cargo recognition, commitment, and unloading drives cotranslational protein targeting.

    Saraogi, Ishu   Akopian, David   Shan, Shu-Ou  

    Efficient and accurate protein localization is essential to cells and requires protein-targeting machineries to both effectively capture the cargo in the cytosol and productively unload the cargo at the membrane. To understand how these challenges are met, we followed the interaction of translating ribosomes during their targeting by the signal recognition particle (SRP) using a site-specific fluorescent probe in the nascent protein. We show that initial recruitment of SRP receptor (SR) selectively enhances the affinity of SRP for correct cargos, thus committing SRP-dependent substrates to the pathway. Real-time measurement of cargo transfer from the targeting to translocation machinery revealed multiple factors that drive this event, including GTPase rearrangement in the SRP-SR complex, stepwise displacement of SRP from the ribosome and signal sequence by SecYEG, and elongation of the nascent polypeptide. Our results elucidate how active and sequential regulation of the SRP-cargo interaction drives efficient and faithful protein targeting. =C2=A9 2014 Saraogi et al.
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  • C–halogen…π interactions in proteins: a database study

    Saraogi, Ishu   Vijay, V.G.   Das, Soma   Sekar, K.   Guru Row, T.N.  

    A Protein Data Bank (PDB) study was undertaken to investigate the role of C–X…π interactions (X=F, Cl, Br, I) in protein structures. From this analysis, it is evident that the propensity for the formation of C–X…π interactions is higher in case of fluorine than in other halogens. These results compare well with the recently reported C–X…π interactions in small molecules and depict the orientational dependence of these interactions.
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  • Synthetic alpha-Helix Mimetics as Agonists and Antagonists of Islet Amyloid Polypeptide Aggregation

    Saraogi, Ishu   Hebda, James A.   Becerril, Jorge   Estroff, Lara A.   Miranker, Andrew D.   Hamilton, Andrew D.  

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  • Characterization of aggregated morphologies derived from mono- and bis-arylbenzamides - potential alpha-helix mimetics

    Kulikov, Oleg V.   Sevryugina, Yulia V.   Mehmood, Arshad   Saraogi, Ishu  

    We report here the synthesis and self-assembly studies of a family of benzamide backbone oligomers bearing various alkyl side chains (e.g., isopropyl, isobutyl, and 2-ethylpentyl), which are potential alpha-helix mimetics capable of disrupting protein-protein interactions. Electron microscopy data (i.e., SEM and TEM concentration series) are indicative of the formation of various aggregates, such as micro-and nanofibers, and spherical beads, which are dominated by bis-oligoamide structures and may have resulted from intermolecular H-bonding, pi-pi stacking, and amide group dipole electrostatic attraction as evidenced by single crystal X-ray analysis. Thus, the aggregation behaviour was shown to depend on the number of repeat units in the oligoamide scaffold featuring elongated aggregates for bis-tetramers, whereas bis-dimers tend to form microspheres in a wide range of concentrations examined. We hypothesize that higher oligomers possessing an extended arylamide backbone are prone to efficiently crystallize with one another by interdigitation of their alkyl side chains leading predominantly to rod-like morphologies and fibrous crystals. The structural findings presented here can be potentially used in the rational design of supramolecular architectures based on arylamide peptidomimetics.
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