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Protein Aggregation and Drug Discove...

Smith, Nathan,

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Protein Aggregation and Drug Discovery for Alzheimer's Disease and Cancer /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Protein Aggregation and Drug Discovery for Alzheimer's Disease and Cancer // Nathan Smith.
Author:	Smith, Nathan,
Description:	1 electronic resource (211 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
Contained By:	Dissertations Abstracts International86-12B.
Subject:	Biochemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31846672
ISBN:	9798280719576

Protein Aggregation and Drug Discovery for Alzheimer's Disease and Cancer /
Smith, Nathan,

Protein Aggregation and Drug Discovery for Alzheimer's Disease and Cancer /Nathan Smith. - 1 electronic resource (211 pages)

Source: Dissertations Abstracts International, Volume: 86-12, Section: B.

Alzheimer's disease (AD) is the most common form of senile dementia, characterized by progressive and irreversible memory loss and impaired cognitive function. The two major pathological hallmarks of AD brains are amyloid plaques in the extracellular space and tau neurofibrillary tangles within neurons. Both forms of protein aggregates spread in a prion-like manner as the disease progresses. Therefore, aggregation inhibitors capable of targeting both amyloid and tau aggregates represent a promising approach for drug development. Carbon dots (CD) can inhibit protein aggregation, which have also demonstrated high biocompatibility, minimal cytotoxicity, and significant blood-brain barrier (BBB) permeability. To develop new drugs to treat AD, CDs have been synthesized from various precursors such as Congo red, citric acid, urea, metformin, and others, and were characterized by Thioflavin T aggregation assays, atomic force microscopy (AFM), transmission electron microscopy (TEM), nuclear magnetic resonance (NMR), and other methods. We found that Congo-red derived CDs (CRCDs) inhibit tau aggregation as well as amyloid-beta aggregation, acting as dual inhibitors. This research offers promising drug candidates for AD drug discovery.For in vitro aggregation experiments, tau requires an inducer, such as heparin, heparan sulfate, or other polyanionic agents. Using ThT, AFM and TEM, we have observed that the sulfation pattern on heparin can affect its ability to induce tau aggregation. Specifically, N-acetylation, or the removal of the N-sulfate group (N-desulfation), results in nearly a total loss of tau aggregation. Interestingly, the removal of the 2-O sulfation and the 6-O sulfation have little effect on the aggregation potential of tau. The importance of N-sulfation was demonstrated in a variety of tau constructs, including full length 2N4R tau, truncated K18 (the microtubule binding region), and tau (188-441) (2N4R with 187 N-terminal residues deleted). Although, variations in the aggregation as a response to N-desulfated heparin was observed between isoforms, specifically observed with increases in concentrations. Other aspects of the heparin-tau interaction to promote aggregation were also investigated such as pH, heparin monosaccharide length, and concentration.Cancer is another leading cause of death in the United States, second only to heart disease, but treatment options are still limited. Two proteins of much interest in cancer research are p53 and CypD. Mutated p53 is present in over half of all human cancers, making it the most important tumor suppressor. Cyclophilin D (CypD) is important in antitumor activity via regulation of apoptosis, necrosis, and mitochondrial permeability by interacting with the mitochondrial permeability transition pore (mPTP). We have shown that CypD binds to the truncated p53 (p53tr) mutants, found in many cancers, including p53 196R*, 213R*, and Ψ. In a subsequent NMR titration, even at the lowest concentrations of p53tr, the mutants bound to CypD and largely reduced its NMR signal. Upon addition of the green tea catechin EGCG, we saw a significant recovery of the CypD signal, suggesting that the binding was partially reversed or inhibited by the presence of EGCG for p53Ψ. This data suggests EGCG, and related polyphenols, may be effective against cancers harboring the p53Ψ mutation. Although, p53-R213* and p53-R196* demonstrated evidence of aggregation and further signal was lost after the addition of EGCG. The oxidation of EGCG, and aggregation potential of p53 and CypD were then explored.

English

ISBN: 9798280719576Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Aggregation

Protein Aggregation and Drug Discovery for Alzheimer's Disease and Cancer /
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520 $a Alzheimer's disease (AD) is the most common form of senile dementia, characterized by progressive and irreversible memory loss and impaired cognitive function. The two major pathological hallmarks of AD brains are amyloid plaques in the extracellular space and tau neurofibrillary tangles within neurons. Both forms of protein aggregates spread in a prion-like manner as the disease progresses. Therefore, aggregation inhibitors capable of targeting both amyloid and tau aggregates represent a promising approach for drug development. Carbon dots (CD) can inhibit protein aggregation, which have also demonstrated high biocompatibility, minimal cytotoxicity, and significant blood-brain barrier (BBB) permeability. To develop new drugs to treat AD, CDs have been synthesized from various precursors such as Congo red, citric acid, urea, metformin, and others, and were characterized by Thioflavin T aggregation assays, atomic force microscopy (AFM), transmission electron microscopy (TEM), nuclear magnetic resonance (NMR), and other methods. We found that Congo-red derived CDs (CRCDs) inhibit tau aggregation as well as amyloid-beta aggregation, acting as dual inhibitors. This research offers promising drug candidates for AD drug discovery.For in vitro aggregation experiments, tau requires an inducer, such as heparin, heparan sulfate, or other polyanionic agents. Using ThT, AFM and TEM, we have observed that the sulfation pattern on heparin can affect its ability to induce tau aggregation. Specifically, N-acetylation, or the removal of the N-sulfate group (N-desulfation), results in nearly a total loss of tau aggregation. Interestingly, the removal of the 2-O sulfation and the 6-O sulfation have little effect on the aggregation potential of tau. The importance of N-sulfation was demonstrated in a variety of tau constructs, including full length 2N4R tau, truncated K18 (the microtubule binding region), and tau (188-441) (2N4R with 187 N-terminal residues deleted). Although, variations in the aggregation as a response to N-desulfated heparin was observed between isoforms, specifically observed with increases in concentrations. Other aspects of the heparin-tau interaction to promote aggregation were also investigated such as pH, heparin monosaccharide length, and concentration.Cancer is another leading cause of death in the United States, second only to heart disease, but treatment options are still limited. Two proteins of much interest in cancer research are p53 and CypD. Mutated p53 is present in over half of all human cancers, making it the most important tumor suppressor. Cyclophilin D (CypD) is important in antitumor activity via regulation of apoptosis, necrosis, and mitochondrial permeability by interacting with the mitochondrial permeability transition pore (mPTP). We have shown that CypD binds to the truncated p53 (p53tr) mutants, found in many cancers, including p53 196R*, 213R*, and Ψ. In a subsequent NMR titration, even at the lowest concentrations of p53tr, the mutants bound to CypD and largely reduced its NMR signal. Upon addition of the green tea catechin EGCG, we saw a significant recovery of the CypD signal, suggesting that the binding was partially reversed or inhibited by the presence of EGCG for p53Ψ. This data suggests EGCG, and related polyphenols, may be effective against cancers harboring the p53Ψ mutation. Although, p53-R213* and p53-R196* demonstrated evidence of aggregation and further signal was lost after the addition of EGCG. The oxidation of EGCG, and aggregation potential of p53 and CypD were then explored.
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653 $a Alzheimer's
653 $a Amyloid
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653 $a Inhibitors
653 $a Thioflavin
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