| 1. |
- Berner, Andreas, et al.
(author)
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G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures
- 2023
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 146:10, s. 6926-6935
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Journal article (peer-reviewed)abstract
- G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.
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| 2. |
- Bose, Partha Pratim, et al.
(author)
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Effects of Congo Red on A beta(1-40) Fibril Formation Process and Morphology
- 2010
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In: ACS CHEMICAL NEUROSCIENCE. - : American Chemical Society (ACS). - 1948-7193. ; 1:4, s. 315-324
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD), an age-related neurodegenerative disorder, is the most common form of dementia, and the seventh-leading cause of death in the United States. Current treatments offer only symptomatic relief; thus, there is a great need for new treatments with disease-modifying potential. One pathological hallmark of AD is so-called senile plaques, mainly made up of beta-sheet-rich assemblies of 40- or 42-residue amyloid beta-peptides (A beta). Hence, inhibition of A beta aggregation is actively explored as an option to prevent or treat AD. Congo red (CR) has been widely used as a model antiamyloid agent to prevent A beta aggregation. Herein, we report detailed morphological studies on the effect of CR as an antiamyloid agent, by circular dichroism spectroscopy, photo-induced cross-linking reactions, and atomic force microscopy. We also demonstrate the effect of CR on a preaggregated sample of A beta(1-40). Our result suggests that A beta(1-40) follows a different path for aggregation in the presence of CR.
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| 3. |
- Bose, Partha Pratim, et al.
(author)
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In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Aβ aggregation
- 2010
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:16, s. 5896-5902
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Journal article (peer-reviewed)abstract
- N-Methylation is a common strategy for improving oral bioavailability of peptide-based lead structures. Herein, we present a detailed study on how the degree of N-methylation affects the absorption-distribution-metabolism-excretion-toxicity (ADMET) properties such as solubility, membrane transport, proteolytic stability, and general cell toxicity of the investigated peptides. As representative structures we chose hexapeptides 1-8. These peptides, corresponding to N-methylated analogues of residues 16-21 and 32-37 of the Abeta-peptide, pathological hallmark of Alzheimer's disease (AD), have previously been shown to inhibit aggregation of Abeta fibrils in vitro. This study suggests that poly-N-methylated peptides are non-toxic and have enhanced proteolytic stability over their non-methylated analogues. Furthermore, solubility in aqueous solution is seen to increase with increased degree of N-methylation, while membrane transport was found to be low for all investigated hexapeptides. The present results, together with those reported in the literature, suggest that poly-N-methylated peptides, especially shorter or equal to six residues, can be suitable candidates for drug design.
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| 4. |
- Bose, Partha Pratim, et al.
(author)
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Template-directed nucleation and growth of CdS nanocrystal : the role of helical and nonhelical nanofibers on their shape and size
- 2010
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In: Journal of nanoparticle research. - : Springer Science and Business Media LLC. - 1388-0764 .- 1572-896X. ; 12:3, s. 713-718
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Journal article (peer-reviewed)abstract
- This study describes the use of chiral nature of synthetic self-assembled nanofibers for nucleation and growth of Cadmium sulfide (CdS) nanocrystals with different sizes and shapes in room temperature. The templates are built by immobilizing a peptide capping agent on the surface of synthetic self-assembled helical or nonhelical nanofibers and CdS nanocrystals were allowed to grow on them. It is observed that there are differences in shapes and sizes of the nanocrystals depending on the chiral nature of the nanofibers on which they were growing. Even the CdS nanocrystals grown on different chiral and achiral nanofibers differ markedly in their photoluminescence properties. Thus, here we introduce a new way of using chirality of nanofibers to nucleate and grow CdS nanocrystals of different shape, size, and optical property.
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| 5. |
- Pratim Bose, Partha, et al.
(author)
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Poly-N-methylated Amyloid β-Peptide (Aβ) C-Terminal Fragments Reduce Aβ Toxicity in Vitro and in Drosophila melanogaster
- 2009
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:24, s. 8002-8009
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid β-peptides (Aβ) into neurotoxic oligo-/polymeric β-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in Aβ aggregation, but most Aβ aggregation inhibitors have targeted the central region around residues 16−23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32−37 of Aβ, to target its C-terminal region. We measured the peptides' abilities to retard β-sheet and fibril formation of Aβ and to reduce Aβ neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human Aβ1−42.
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