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Dive into the research topics where Janarthanan Krishnamoorthy is active.

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Featured researches published by Janarthanan Krishnamoorthy.


Journal of the American Chemical Society | 2014

Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer's Disease

SangHyun Lee; Xueyun Zheng; Janarthanan Krishnamoorthy; Masha G. Savelieff; Hyun Min Park; Jeffrey R. Brender; Jin Hoon Kim; Jeffrey S. Derrick; Akiko Kochi; Hyuck Jin Lee; Cheal Kim; Ayyalusamy Ramamoorthy; Michael T. Bowers; Mi Hee Lim

Alzheimers disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound Aβ (metal-Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal-Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.


Biochemistry | 2013

Resolution of Oligomeric Species during the Aggregation of Aβ1–40 Using 19F NMR

Yuta Suzuki; Jeffrey R. Brender; Molly T. Soper; Janarthanan Krishnamoorthy; Yunlong Zhou; Brandon T. Ruotolo; Nicholas A. Kotov; Ayyalusamy Ramamoorthy; E. Neil G. Marsh

In the commonly used nucleation-dependent model of protein aggregation, aggregation proceeds only after a lag phase in which the concentration of energetically unfavorable nuclei reaches a critical value. The formation of oligomeric species prior to aggregation can be difficult to detect by current spectroscopic techniques. By using real-time (19)F NMR along with other techniques, we are able to show that multiple oligomeric species can be detected during the lag phase of Aβ1-40 fiber formation, consistent with a complex mechanism of aggregation. At least six types of oligomers can be detected by (19)F NMR. These include the reversible formation of large β-sheet oligomer immediately after solubilization at high peptide concentration, a small oligomer that forms transiently during the early stages of the lag phase, and four spectroscopically distinct forms of oligomers with molecular weights between ∼30 and 100 kDa that appear during the later stages of aggregation. The ability to resolve individual oligomers and track their formation in real-time should prove fruitful in understanding the aggregation of amyloidogenic proteins and in isolating potentially toxic nonamyloid oligomers.


Chemical Communications | 2013

Zinc stabilization of prefibrillar oligomers of human islet amyloid polypeptide

Jeffrey R. Brender; Janarthanan Krishnamoorthy; Grazia M. L. Messina; Aniruddha Deb; Subramanian Vivekanandan; Carmelo La Rosa; James E. Penner-Hahn; Ayyalusamy Ramamoorthy

The aggregation of human islet amyloid polypeptide (hIAPP) has been linked to beta-cell death in type II diabetes. Zinc present in secretory granules has been shown to affect this aggregation. A combination of EXAFS, NMR, and AFM experiments shows that the influence of zinc is most likely due to the stabilization of prefibrillar aggregates of hIAPP.


ChemMedChem | 2014

Indolicidin Targets Duplex DNA: Structural and Mechanistic Insight through a Combination of Spectroscopy and Microscopy

Anirban Ghosh; Rajiv Kumar Kar; Jagannath Jana; Abhijit Saha; Batakrishna Jana; Janarthanan Krishnamoorthy; Dinesh Kumar; Surajit Ghosh; Subhrangsu Chatterjee; Anirban Bhunia

Indolicidin (IR13), a 13‐residue antimicrobial peptide from the cathelicidin family, is known to exhibit a broad spectrum of antimicrobial activity against various microorganisms. This peptide inhibits bacterial DNA synthesis resulting in cell filamentation. However, the precise mechanism remains unclear and requires further investigation. The central PWWP motif of IR13 provides a unique structural element that can wrap around, and thus stabilize, duplex B‐type DNA structures. Replacements of the central Trp‐Trp pair with Ala‐Ala, His‐His, or Phe‐Phe residues in the PxxP motif significantly affects the ability of the peptide to stabilize duplex DNA. Results of microscopy studies in conjunction with spectroscopic data confirm that the DNA duplex is stabilized by IR13, thereby inhibiting DNA replication and transcription. In this study we provide high‐resolution structural information on the interaction between indolicidin and DNA, which will be beneficial for the design of novel therapeutic antibiotics based on peptide scaffolds.


Biochemistry | 2013

Lipid composition-dependent membrane fragmentation and pore-forming mechanisms of membrane disruption by pexiganan (MSI-78).

Dong Kuk Lee; Jeffrey R. Brender; Michele F.M. Sciacca; Janarthanan Krishnamoorthy; Changsu Yu; Ayyalusamy Ramamoorthy

The potency and selectivity of many antimicrobial peptides (AMPs) are correlated with their ability to interact with and disrupt the bacterial cell membrane. In vitro experiments using model membranes have been used to determine the mechanism of membrane disruption of AMPs. Because the mechanism of action of an AMP depends on the ability of the model membrane to accurately mimic the cell membrane, it is important to understand the effect of membrane composition. Anionic lipids that are present in the outer membrane of prokaryotes but are less common in eukaryotic membranes are usually thought to be key for the bacterial selectivity of AMPs. We show by fluorescence measurements of peptide-induced membrane permeabilization that the presence of anionic lipids at high concentrations can actually inhibit membrane disruption by the AMP MSI-78 (pexiganan), a representative of a large class of highly cationic AMPs. Paramagnetic quenching studies suggest MSI-78 is in a surface-associated inactive mode in anionic sodium dodecyl sulfate micelles but is in a deeply buried and presumably more active mode in zwitterionic dodecylphosphocholine micelles. Furthermore, a switch in mechanism occurs with lipid composition. Membrane fragmentation with MSI-78 can be observed in mixed vesicles containing both anionic and zwitterionic lipids but not in vesicles composed of a single lipid of either type. These findings suggest membrane affinity and membrane permeabilization are not always correlated, and additional effects that may be more reflective of the actual cellular environment can be seen as the complexity of the model membranes is increased.


Scientific Reports | 2015

High-resolution NMR characterization of low abundance oligomers of amyloid-β without purification

Samuel A. Kotler; Jeffrey R. Brender; Subramanian Vivekanandan; Yuta Suzuki; Kazutoshi Yamamoto; Martine Monette; Janarthanan Krishnamoorthy; Patrick Walsh; Meagan Cauble; Mark M. Banaszak Holl; E. Neil G. Marsh; Ayyalusamy Ramamoorthy

Alzheimer’s disease is characterized by the misfolding and self-assembly of the amyloidogenic protein amyloid-β (Aβ). The aggregation of Aβ leads to diverse oligomeric states, each of which may be potential targets for intervention. Obtaining insight into Aβ oligomers at the atomic level has been a major challenge to most techniques. Here, we use magic angle spinning recoupling 1H-1H NMR experiments to overcome many of these limitations. Using 1H-1H dipolar couplings as a NMR spectral filter to remove both high and low molecular weight species, we provide atomic-level characterization of a non-fibrillar aggregation product of the Aβ1-40 peptide using non-frozen samples without isotopic labeling. Importantly, this spectral filter allows the detection of the specific oligomer signal without a separate purification procedure. In comparison to other solid-state NMR techniques, the experiment is extraordinarily selective and sensitive. A resolved 2D spectra could be acquired of a small population of oligomers (6 micrograms, 7% of the total) amongst a much larger population of monomers and fibers (93% of the total). By coupling real-time 1H-1H NMR experiments with other biophysical measurements, we show that a stable, primarily disordered Aβ1-40 oligomer 5–15 nm in diameter can form and coexist in parallel with the well-known cross-β-sheet fibrils.


Journal of Physical Chemistry B | 2015

Probing the Sources of the Apparent Irreproducibility of Amyloid Formation: Drastic Changes in Kinetics and a Switch in Mechanism Due to Micellelike Oligomer Formation at Critical Concentrations of IAPP

Jeffrey R. Brender; Janarthanan Krishnamoorthy; Michele F.M. Sciacca; Subramanian Vivekanandan; Luisa D’Urso; Jennifer Y. Chen; Carmelo La Rosa; Ayyalusamy Ramamoorthy

The aggregation of amyloidogenic proteins is infamous for being highly chaotic, with small variations in conditions sometimes leading to large changes in aggregation rates. Using the amyloidogenic protein IAPP (islet amyloid polypeptide protein, also known as amylin) as an example, we show that a part of this phenomenon may be related to the formation of micellelike oligomers at specific critical concentrations and temperatures. We show that pyrene fluorescence can sensitively detect micellelike oligomer formation by IAPP and discriminate between micellelike oligomers from fibers and monomers, making pyrene one of the few chemical probes specific to a prefibrillar oligomer. We further show that oligomers of this type reversibly form at critical concentrations in the low micromolar range and at specific critical temperatures. Micellelike oligomer formation has several consequences for amyloid formation by IAPP. First, the kinetics of fiber formation increase substantially as the critical concentration is approached but are nearly independent of concentration below it, suggesting a direct role for the oligomers in fiber formation. Second, the critical concentration is strongly correlated with the propensity to form amyloid: higher critical concentrations are observed for both IAPP variants with lower amyloidogenicity and for native IAPP at acidic pH in which aggregation is greatly slowed. Furthermore, using the DEST NMR technique, we show that the pathway of amyloid formation switches as the critical point is approached, with self-interactions primarily near the N-terminus below the critical temperature and near the central region above the critical temperature, reconciling two apparently conflicting views of the initiation of IAPP aggregation.


Chemical Science | 2014

Interaction and reactivity of synthetic aminoisoflavones with metal-free and metal-associated amyloid-β

Alaina S. DeToma; Janarthanan Krishnamoorthy; Younwoo Nam; Hyuck Jin Lee; Jeffrey R. Brender; Akiko Kochi; Dong-Kuk Lee; Valentina Onnis; Cenzo Congiu; Stefano Manfredini; Silvia Vertuani; Gianfranco Balboni; Ayyalusamy Ramamoorthy; Mi Hee Lim

Metal ion homeostasis in conjunction with amyloid-β (Aβ) aggregation in the brain has been implicated in Alzheimers disease (AD) pathogenesis. To uncover the interplay between metal ions and Aβ peptides, synthetic, multifunctional small molecules have been employed to modulate Aβ aggregation in vitro. Naturally occurring flavonoids have emerged as a valuable class of compounds for this purpose due to their ability to control both metal-free and metal-induced Aβ aggregation. Although flavonoids have shown anti-amyloidogenic effects, the structural moieties of flavonoids responsible for such reactivity have not been fully identified. In order to understand the structure–interaction–reactivity relationship within the flavonoid family for metal-free and metal-associated Aβ, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1–4), that displayed reactivity (i.e., modulation of Aβ aggregation) in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix of prefibrillar Aβ, which is different from the non-specific binding observed for other flavonoids. The absence or presence of the catechol group, responsible for metal binding, differentiated the binding affinities of aminoisoflavones with Aβ and enthalpy/entropy balance for their Aβ interaction. Furthermore, having a catechol group influenced the binding mode with fibrillar Aβ. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on Aβ aggregation. Overall, through these studies, we obtained valuable insights into the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for Aβ interaction.


Biochemical and Biophysical Research Communications | 2014

Potent γ-secretase inhibitors/modulators interact with amyloid-β fibrils but do not inhibit fibrillation: A high-resolution NMR study

Ravichandran Yesuvadian; Janarthanan Krishnamoorthy; Ayyalusamy Ramamoorthy; Anirban Bhunia

Recently, γ-secretase modulators (GSM) have been shown to interact directly with the amyloid precursor protein (APP) and simultaneously inhibit the activity of the Presenilin domain of γ-secretase. A clear understanding of the molecular recognition pathways by which GSM can target both γ-secretase and Aβ precursor protein can lead to the development of more effective inhibitors. To examine whether this direct interaction with APP affects the downstream Aβ fibril formation, we chose to investigate three different molecules in this study: Sulindac sulfide, Semagacestat and E2012 from the class of generation I GSMs, γ-secretase inhibitors (GSI), and generation II GSM molecules, respectively. Firstly, through NMR based ligand titration, we identified that Sulindac sulfide and Semagacestat interact strongly with Aβ40 monomers, whereas E2012 does not. Secondly, using saturation transfer difference (STD) NMR experiments, we found that all three molecules bind equally well with Aβ40 fibrils. To determine if these interactions with the monomer/fibril lead to a viable inhibition of the fibrillation process, we designed an NMR based time-dependent assay and accurately distinguished the inhibitors from the non-inhibitors within a short period of 12h. Based on this pre-seeded fibril assay, we conclude that none of these molecules inhibit the ongoing fibrillation, rather ligands such as Semagacestat and E2012 accelerated the rate of aggregation.


The Royal Society of Chemistry | 2014

Synthetic Flavonoids, Aminoisoflavones: Interaction and Reactivity with Metal-Free and Metal-Associated Amyloid-β Species

Alaina S. DeToma; Janarthanan Krishnamoorthy; Younwoo Nam; Hyuck Jin Lee; Jeffrey R. Brender; Akiko Kochi; Dong-Kuk Lee; Valentina Onnis; Cenzo Congiu; Stefano Manfredini; Silvia Vertuani; Gianfranco Balboni; Ayyalusamy Ramamoorthy; Mi Hee Lim

Metal ion homeostasis in conjunction with amyloid-β (Aβ) aggregation in the brain has been implicated in Alzheimers disease (AD) pathogenesis. To uncover the interplay between metal ions and Aβ peptides, synthetic, multifunctional small molecules have been employed to modulate Aβ aggregation in vitro. Naturally occurring flavonoids have emerged as a valuable class of compounds for this purpose due to their ability to modulate both metal-free and metal-induced Aβ aggregation. Although, flavonoids have shown anti-amyloidogenic effects, the structural moieties of flavonoids responsible for such reactivity have not been fully identified. In order to understand the structure-interaction-reactivity relationship within the flavonoid family for metal-free and metal-associated Aβ, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1-4), that displayed reactivity (i.e., modulation of Aβ aggregation) in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix on prefibrillar Aβ different from the non-specific binding observed for other flavonoids. The absence or presence of the catechol group differentiated the binding affinities and enthalpy/entropy balance between aminoisoflavones and Aβ. Furthermore, having a catechol group influenced the binding mode with fibrillar Aβ. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on Aβ aggregation. Overall, through these studies, we obtained valuable insights on the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for Aβ interaction.

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Akiko Kochi

University of Michigan

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Hyuck Jin Lee

Ulsan National Institute of Science and Technology

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Mi Hee Lim

Ulsan National Institute of Science and Technology

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