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Antibacterial sulfo...
Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors : Synthesis and biological evaluation
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- Benediktsdottir, Andrea, 1990- (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling,Uppsala University
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- Lu, Lu, 1984- (author)
- Uppsala universitet,Strukturbiologi
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- Cao, Sha (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Zamaratski, Edouard (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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- Karlén, Anders (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Mowbray, Sherry L, 1954- (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab
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- Hughes, Diarmaid, 1956- (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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- Sandström, Anja, 1973- (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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(creator_code:org_t)
- Elsevier, 2021
- 2021
- English.
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 224
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation. Unfortunately, this modification is associated with cytotoxicity, motivating the need for novel approaches. The sulfonimidamide functionality has recently gained much interest in drug design and discovery, as a means of introducing chirality and an imine-handle, thus allowing for the incorporation of additional substituents. This in turn can tune the chemical and biological properties, which are here explored. We show that introducing the sulfonimidamide between the lipophilic tail and the peptide in a series of signal peptidase inhibitors resulted in antibacterial activity, while the sulfonamide isostere and previously known non-cationic analogs were inactive. Additionally, we show that replacing the sulfonamide with a sulfonimidamide resulted in decreased cytotoxicity, and similar results were seen by adding a cationic sidechain to the sulfonimidamide motif. This is the first report of incorporation of the sulfonimidamide functional group into bioactive peptides, more specifically into antibacterial oligopeptides, and evaluation of its biological effects.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Antibacterial
- Bacterial type I Signal peptidase
- Bioisosteres
- LepB
- Oligopeptides
- Serine-lysine protease
- Sulfonimidamide
- Kemi med inriktning mot organisk kemi
- Chemistry with specialization in Organic Chemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Benediktsdottir, ...
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Lu, Lu, 1984-
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Cao, Sha
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Zamaratski, Edou ...
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Karlén, Anders
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Mowbray, Sherry ...
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show more...
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Hughes, Diarmaid ...
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Sandström, Anja, ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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European Journal ...
- By the university
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Uppsala University