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The design and synthesis of stereodiverse scaffolds.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The design and synthesis of stereodiverse scaffolds.
作者:	Gierasch, Tiffany Kaye Malinky.
面頁冊數:	197 p.
附註:	Adviser: Gregory L. Verdine.
附註:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0212.
Contained By:	Dissertation Abstracts International64-01B.
標題:	Chemistry, Organic.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3076884
ISBN:	049397346X

The design and synthesis of stereodiverse scaffolds.
Gierasch, Tiffany Kaye Malinky.

The design and synthesis of stereodiverse scaffolds. [electronic resource] - 197 p.

Adviser: Gregory L. Verdine.

Thesis (Ph.D.)--Harvard University, 2003.

As an extension of our results with renin, we synthesized beta-secretase peptides containing scaffold B and assayed them for inhibition. Quite surprisingly, these peptides were only modest inhibitors, displaying IC50 values in the 100--200 muM range. Application of scaffold C, which is related to scaffold B by a methylene transposition, provided similar levels of moderate inhibition. The loss of potency was postulated to derive from the more open orientation of the active site cleft of beta-secretase compared to renin, making it a more challenging target due to the decreased surface area available for attractive interactions. Comparison of the results between these two superficially similar enzymes highlights the need for diversity of all types in the identification of biologic ligands and underscores the need for unbiased approaches to ligand discovery.

ISBN: 049397346XSubjects--Topical Terms:

193634
Chemistry, Organic.

The design and synthesis of stereodiverse scaffolds.
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502 $a Thesis (Ph.D.)--Harvard University, 2003.
520 $a As an extension of our results with renin, we synthesized beta-secretase peptides containing scaffold B and assayed them for inhibition. Quite surprisingly, these peptides were only modest inhibitors, displaying IC50 values in the 100--200 muM range. Application of scaffold C, which is related to scaffold B by a methylene transposition, provided similar levels of moderate inhibition. The loss of potency was postulated to derive from the more open orientation of the active site cleft of beta-secretase compared to renin, making it a more challenging target due to the decreased surface area available for attractive interactions. Comparison of the results between these two superficially similar enzymes highlights the need for diversity of all types in the identification of biologic ligands and underscores the need for unbiased approaches to ligand discovery.
520 $a Peptides containing scaffold A were screened for their ability to inhibit renin. These peptides were moderate inhibitors with the most potent compounds having IC50 values in the low micromolar range. Interestingly, these peptides displayed very different lipophilicities among the various stereoisomers, inspiring us to consider the use of stereochemical diversity not only to optimize ligand affinity, but perhaps to modulate other pharmacological parameters. Peptides containing scaffold B were synthesized in an effort to improve the potency of renin inhibitors. This second library resulted in several low nanomolar inhibitors, indicating that scaffold B is more suited to inhibitors of renin than scaffold A. Importantly, a stereochemical preference among these inhibitors was discovered which would not have been predicted based on literature precedent.
520 $a This thesis describes our efforts to use stereochemistry as a diversity element in the design and synthesis of aspartyl protease inhibitors. Three different acyclic scaffolds are described, as well as related derivatives accessed through further diversification of the scaffold backbone. These scaffolds were embedded into peptides representing the recognition sequence of two enzymes, renin and beta-secretase. They were inserted over the cleavage site where it was envisioned they would mimic the developing tetrahedral character of the transition state, providing tight binding inhibitors.
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