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Design of membrane-lytic peptides.

Haas, David H.

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Design of membrane-lytic peptides.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Design of membrane-lytic peptides./
Author:	Haas, David H.
Description:	161 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1978.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Engineering, Chemical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128132
ISBN:	9780496753956

Design of membrane-lytic peptides.
Haas, David H.

Design of membrane-lytic peptides. - 161 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1978.

Thesis (Ph.D.)--The University of Wisconsin - Madison, 2004.

Novel medicinal compounds designed to treat diseases such as cancer require targeted delivery to precise cellular compartments. The effectiveness of these compounds is limited by poor transport across intracellular membranes. Incorporation of membrane-disrupting peptides into these systems may improve transport. Such peptides cause localized disruptions of lipid bilayers and permit passage of molecules otherwise unable to cross cellular membranes. While studies using membrane disruptive peptides have demonstrated their promise, obstacles such as low peptide activity and toxicity need to be overcome for practical use.

ISBN: 9780496753956Subjects--Topical Terms:

1018531
Engineering, Chemical.

Design of membrane-lytic peptides.
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020 $a 9780496753956
035 $a (UnM)AAI3128132
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040 $a UnM $c UnM
100 1 $a Haas, David H. $3 1910164
245 1 0 $a Design of membrane-lytic peptides.
300 $a 161 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1978.
500 $a Supervisor: Regina M. Murphy.
502 $a Thesis (Ph.D.)--The University of Wisconsin - Madison, 2004.
520 $a Novel medicinal compounds designed to treat diseases such as cancer require targeted delivery to precise cellular compartments. The effectiveness of these compounds is limited by poor transport across intracellular membranes. Incorporation of membrane-disrupting peptides into these systems may improve transport. Such peptides cause localized disruptions of lipid bilayers and permit passage of molecules otherwise unable to cross cellular membranes. While studies using membrane disruptive peptides have demonstrated their promise, obstacles such as low peptide activity and toxicity need to be overcome for practical use.
520 $a The focus of this work was the design of improved peptides for drug delivery. The peptide GALA was chosen as a starting point based on its pH-sensitive nature and structural similarities with other lytic peptides. We hypothesized that changes to its structure and sequence would result in peptides more suitable for drug delivery applications.
520 $a We examined if the placement of multiple copies of GALA onto a template peptide would increase GALA's membrane lytic activity without adversely affecting its pH sensitivity. Three peptides were synthesized, containing 2 or 3 copies of GALA variably spaced along the template molecule. Templates containing 2 attached GALA had similar per-peptide activity as the monomer, while templates with 3 attached GALA were less active on a per-peptide basis, with a dramatic loss of activity when a long and flexible spacer was used. Altered binding of templated GALA to lipid membranes and cyclization of template GALA aggregates may explain this loss of activity. The pH sensitivity of GALA was not affected by template attachment.
520 $a Modifications of the primary sequence of GALA were made to create a peptide with improved biological utility. Two derivatives were prepared in which glutamate residues were removed (GALAdel3E) or replaced with 3,5-diiodotyrosine (YALA). Both GALAdel3E and YALA possessed altered pH sensitivity compared to GALA, with the onset of lytic activity occurring roughly 0.5 and 1.0 pH unit higher than GALA, respectively. YALA, and to a smaller extent GALAdel3E, retained a greater fraction of lytic activity in membranes containing cholesterol than did GALA, making YALA a superior peptide to GALA for cellular delivery of medicinal compounds.
590 $a School code: 0262.
650 4 $a Engineering, Chemical. $3 1018531
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0542
690 $a 0419
710 2 0 $a The University of Wisconsin - Madison. $3 626640
773 0 $t Dissertation Abstracts International $g 65-04B.
790 1 0 $a Murphy, Regina M., $e advisor
790 $a 0262
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3128132