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The design, synthesis, and biophysic...

Johnson, Steven M.

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The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis./
作者:	Johnson, Steven M.
面頁冊數:	409 p.
附註:	Source: Dissertation Abstracts International, Volume: 67-03, Section: B, page: 1447.
Contained By:	Dissertation Abstracts International67-03B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3210288
ISBN:	9780542590863

The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis.
Johnson, Steven M.

The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis. - 409 p.

Source: Dissertation Abstracts International, Volume: 67-03, Section: B, page: 1447.

Thesis (Ph.D.)--The Scripps Research Institute, 2006.

Small molecule-mediated protein stabilization is a promising strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Small molecule binding to the thyroxine binding sites within TTR causes preferential stabilization of the protein's native state over the dissociative transition state, raising the kinetic barrier of dissociation and preventing amyloidogenesis. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits kinetically stabilizes TTR and ameliorates amyloidosis in humans, a small molecule based therapy will likely alleviate TTR amyloidosis as well.

ISBN: 9780542590863Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis.
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245 1 4 $a The design, synthesis, and biophysical evaluation of small molecules to study and selectively inhibit transthyretin amyloidosis.
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520 $a Small molecule-mediated protein stabilization is a promising strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Small molecule binding to the thyroxine binding sites within TTR causes preferential stabilization of the protein's native state over the dissociative transition state, raising the kinetic barrier of dissociation and preventing amyloidogenesis. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits kinetically stabilizes TTR and ameliorates amyloidosis in humans, a small molecule based therapy will likely alleviate TTR amyloidosis as well.
520 $a Allosteric interactions between transthyretin's two thyroxine binding sites causes inhibitors to bind with either positive, non-, or in most cases negative cooperativity. Assessing the amyloidogenicity of a TTR tetramer with only one inhibitor (I) bound is challenging because the small molecule binding constants do not allow the exclusive formation of TTR•I in solution to the exclusion of TTR•I2 and unliganded TTR. By tethering one inhibitor to TTR it is established that single site occupancy can impose kinetic stabilization on the entire tetrameric structure and prevent amyloidogenesis. This suggests it may be possible to employ lower therapeutic concentrations of amyloidosis inhibitors than previously thought necessary to maintain efficacy, which could mitigate toxicity in the envisioned long tern therapy provided the inhibitors bind selectively to TTR over the plethora of other proteins in the blood.
520 $a Unfortunately, the majority of the 200 or so potent small molecule amyloidogenesis inhibitors do not bind selectively to TTR. In an effort to create potent amyloidogenesis inhibitors with increased TTR binding selectivity (while minimizing interactions with the thyroid hormone nuclear receptor and COX-1), three small molecule libraries were designed to systematically screen the structural elements comprising a typical inhibitor: the two aryl substructures and the linker joining them. The structure-reactivity relationships (SAR) derived from these studies effectively predict the potency and selectivity of structurally diverse small molecule inhibitors both within the scope of, or isostructural with inhibitors encompassed by the SAR. With such a powerful predictive tool available the chance of successfully developing an effective clinical candidate is dramatically increased.
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