ArticleThe Journal of biological chemistry2015
Efflux by small multidrug resistance proteins is inhibited by membrane-interactive helix-stapled peptides.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Antimicrobial Peptides as Antibiotic Adjuvants: Overcoming Resistance through Multifaceted Mechanisms.Probiotics and antimicrobial proteins · 2026Article
- Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation.RSC medicinal chemistry · 2023Review
- Peptide Stapling Applied to Antimicrobial Peptides.Antibiotics (Basel, Switzerland) · 2023Review
- Development of Bifunctional, Raman Active Diyne-Girder Stapled α-Helical Peptides.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Still rocking in the structural era: A molecular overview of the small multidrug resistance (SMR) transporter family.The Journal of biological chemistry · 2022Review
- Transmembrane peptide effects on bacterial membrane integrity and organization.Biophysical journal · 2022Article
- Identification of CTL Epitopes on Efflux Pumps of the ATP-Binding Cassette and the Major Facilitator Superfamily ofJournal of immunology research · 2021Article
- Peptide-Based Efflux Pump Inhibitors of the Small Multidrug Resistance Protein from Pseudomonas aeruginosa.Antimicrobial agents and chemotherapy · 2019Article
- Structure of theProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Stapling strategy enables improvement of antitumor activity and proteolytic stability of host-defense peptide hymenochirin-1B.RSC advances · 2018Article
- Targeting the Channel Activity of Viroporins.Advances in protein chemistry and structural biology · 2016Review
- Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals?Viruses · 2015Review
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Bacterial cell membranes contain several protein pumps that resist the toxic effects of drugs by efficiently extruding them. One family of these pumps, the small multidrug resistance proteins (SMRs), consists of proteins of about 110 residues that need to oligomerize to form a structural pathway for substrate extrusion. As such, SMR oligomerization sites should constitute viable targets for efflux inhibition, by disrupting protein-protein interactions between helical segments. To explore this proposition, we are using Hsmr, an SMR from Halobacter salinarum that dimerizes to extrude toxicants. Our previous work established that (i) Hsmr dimerization is mediated by a helix-helix interface in Hsmr transmembrane (TM) helix 4 (residues (90)GLALIVAGV(98)); and (ii) a peptide comprised of the full TM4(85-105) sequence inhibits Hsmr-mediated ethidium bromide efflux from bacterial cells. Here we define the minimal linear sequence for inhibitor activity (determined as TM4(88-100), and then "staple" this sequence via Grubbs metathesis to produce peptides typified by acetyl-A-(Sar)3-(88)VVGLXLIZXGVVV(100)-KKK-NH2 (X = 2-(4'-pentenyl)alanine at positions 92 and 96; Z = Val, Gly, or Asn at position 95)). The Asn(95) peptide displayed specific efflux inhibition and resensitization of Hsmr-expressing cells to ethidium bromide; and was non-hemolytic to human red blood cells. Stapling essentially prevented peptide degradation in blood plasma and liver homogenates versus an unstapled counterpart. The overall results confirm that the stapled analog of TM4(88-100) retains the structural complementarity required to disrupt the Hsmr TM4-TM4 locus in Hsmr, and portend the general validity of stapled peptides as therapeutics for the disruption of functional protein-protein interactions in membranes.
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