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JOURNAL ARTICLE
Yihui Wang, Joseph P Hoffmann, Chau-Wen Chou, Kerstin Höner Zu Bentrup, Joseph A Fuselier, Jacob P Bitoun, William C Wimley, Lisa A Morici
Gram-negative bacteria secrete outer membrane vesicles (OMVs) that play critical roles in intraspecies, interspecies, and bacteria-environment interactions. Some OMVs, such as those produced by Pseudomonas aeruginosa, have previously been shown to possess antimicrobial activity against competitor species. In the current study, we demonstrate that OMVs from Burkholderia thailandensis inhibit the growth of drug-sensitive and drug-resistant bacteria and fungi. We show that a number of antimicrobial compounds, including peptidoglycan hydrolases, 4-hydroxy-3-methyl-2-(2-non-enyl)-quinoline (HMNQ) and long-chain rhamnolipid are present in or tightly associate with B...
July 2020: Journal of Microbiology / the Microbiological Society of Korea
#22
JOURNAL ARTICLE
Charles G Starr, Jenisha Ghimire, Shantanu Guha, Joseph P Hoffmann, Yihui Wang, Leisheng Sun, Brooke N Landreneau, Zachary D Kolansky, Isabella M Kilanowski-Doroh, Mimi C Sammarco, Lisa A Morici, William C Wimley
Novel classes of antibiotics and new strategies to prevent and treat infections are urgently needed because the rapid rise in drug-resistant bacterial infections in recent decades has been accompanied by a parallel decline in development of new antibiotics. Membrane permeabilizing antimicrobial peptides (AMPs) have long been considered a potentially promising, novel class of antibiotic, especially for wound protection and treatment to prevent the development of serious infections. Yet, despite thousands of known examples, AMPs have only infrequently proceeded as far as clinical trials, especially the chemically simple, linear examples...
April 14, 2020: Proceedings of the National Academy of Sciences of the United States of America
#23
JOURNAL ARTICLE
Peng Liao, Nimisha Bhattarai, Bo Cao, Xiang Zhou, Ji Hoon Jung, Krishna Damera, Taylor T Fuselier, Suresh Thareja, William C Wimley, Binghe Wang, Shelya X Zeng, Hua Lu
Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays...
April 9, 2020: Biochemical and Biophysical Research Communications
#24
REVIEW
William C Wimley
Despite long-standing promise and many known examples, antimicrobial peptides (AMPs) have failed, with few exceptions, to significantly impact human medicine. Impediments to the systemic activity of AMPs include proteolysis, host cell interactions, and serum protein binding, factors that are not often considered in the early stages of AMP development. Here we discuss how synthetic molecular evolution, iterative cycles of library design, and physiologically relevant screening can be used to evolve AMPs that do not have these impediments...
2019: Advances in Experimental Medicine and Biology
#25
JOURNAL ARTICLE
Sarah Y Kim, Anna E Pittman, Elmer Zapata-Mercado, Gavin M King, William C Wimley, Kalina Hristova
Using synthetic molecular evolution, we previously discovered a family of peptides that cause macromolecular poration in synthetic membranes at low peptide concentration in a way that is triggered by acidic pH. To understand the mechanism of action of these "pHD peptides", here we systematically explored structure-function relationships through measurements of the effect of pH and peptide concentration on membrane binding, peptide structure, and the formation of macromolecular-sized pores in membranes. Both AFM and functional assays demonstrate the peptide-induced appearance of large pores in bilayers...
April 24, 2019: Journal of the American Chemical Society
#26
JOURNAL ARTICLE
Charles H Chen, Charles G Starr, Evan Troendle, Gregory Wiedman, William C Wimley, Jakob P Ulmschneider, Martin B Ulmschneider
In the age of failing small-molecule antibiotics, tapping the near-infinite structural and chemical repertoire of antimicrobial peptides (AMPs) offers one of the most promising routes toward developing next-generation antibacterial compounds. One of the key impediments en route is the lack of methodologies for systematic rational design and optimization of new AMPs. Here we present a new simulation-guided rational design approach and apply it to develop a potent new AMP. We show that unbiased atomic detail molecular dynamics (MD) simulations are able to predict structures formed by evolving peptide designs enabling structure-based rational fine-tuning of functional properties...
March 27, 2019: Journal of the American Chemical Society
#27
JOURNAL ARTICLE
Samantha L Gerlach, Partha K Chandra, Upal Roy, Sunithi Gunasekera, Ulf Göransson, William C Wimley, Stephen E Braun, Debasis Mondal
Background: Novel strategies to increase the efficacy of antiretroviral (ARV) drugs will be of crucial importance. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Methods: Physiologically safe concentrations of CyO2 were determined via red blood cell (RBC) hemolysis. SYTOX-green dye-uptake and radiolabeled saquinavir (³H-SQV) uptake assays were used to measure pore-formation and drug uptake, respectively...
February 28, 2019: Medicines (Basel, Switzerland)
#28
JOURNAL ARTICLE
Shantanu Guha, Jenisha Ghimire, Eric Wu, William C Wimley
Membrane permeabilizing peptides (MPPs) are as ubiquitous as the lipid bilayer membranes they act upon. Produced by all forms of life, most membrane permeabilizing peptides are used offensively or defensively against the membranes of other organisms. Just as nature has found many uses for them, translational scientists have worked for decades to design or optimize membrane permeabilizing peptides for applications in the laboratory and in the clinic ranging from antibacterial and antiviral therapy and prophylaxis to anticancer therapeutics and drug delivery...
January 9, 2019: Chemical Reviews
#29
JOURNAL ARTICLE
W Berkeley Kauffman, Shantanu Guha, William C Wimley
Peptides and analogs such as peptide nucleic acids (PNA) are promising tools and therapeutics, but the cell membrane remains a barrier to intracellular targets. Conjugation to classical cell penetrating peptides (CPPs) such as pTat48-60 (tat) and pAntp43-68 (penetratin) facilitates delivery; however, efficiencies are low. Lack of explicit design principles hinders rational improvement. Here, we use synthetic molecular evolution (SME) to identify gain-of-function CPPs with dramatically improved ability to deliver cargoes to cells at low concentration...
July 2, 2018: Nature Communications
#30
JOURNAL ARTICLE
Sijia Li, Sarah Y Kim, Anna E Pittman, Gavin M King, William C Wimley, Kalina Hristova
Pore-forming peptides with novel functions have potential utility in many biotechnological applications. However, the sequence-structure-function relationships of pore forming peptides are not understood well enough to empower rational design. Therefore, in this work, we used synthetic molecular evolution to identify a novel family of peptides that are highly potent and cause macromolecular poration in synthetic lipid vesicles at low peptide concentration and at neutral pH. These unique 26-residue peptides, which we call macrolittins, release macromolecules from lipid bilayer vesicles made from zwitterionic PC lipids at peptide to lipid ratios as low as 1:1000, a property that is almost unprecedented among known membrane permeabilizing peptides...
May 23, 2018: Journal of the American Chemical Society
#31
JOURNAL ARTICLE
William C Wimley
No abstract text is available yet for this article.
January 23, 2018: Biophysical Journal
#32
JOURNAL ARTICLE
Charles G Starr, William C Wimley
Well-studied and promising antimicrobial peptides (AMPs), with potent bactericidal activity, in vitro, have yet to have a significant impact in human medicine beyond topical applications. We previously showed that interactions of AMPs with concentrated human erythrocytes inhibit many of them, and suggested that screens and assays should be done in their presence to mimic host cell inhibition. Here, we use AMPs to characterize the activity of proteases that are associated with human erythrocytes. The representative AMPs, ARVA and indolicidin, are degraded significantly during incubation with dilute, washed erythrocytes and yield a variety of degradation products, suggesting significant exopeptidase activity...
December 2017: Biochimica et Biophysica Acta
#33
JOURNAL ARTICLE
Taylor Fuselier, William C Wimley
We previously used an orthogonal high-throughput screen to select peptides that spontaneously cross synthetic lipid bilayers without bilayer disruption. Many of the 12-residue spontaneous membrane translocating peptides (SMTPs) selected from the library contained a 5-residue consensus motif, LRLLR in positions 5-9. We hypothesized that the conserved motif could be a necessary and sufficient minimal motif for translocation. To test this and to explore the mechanism of spontaneous membrane translocation, we synthesized seven arginine placement variants of LRLLRWC and compared their membrane partitioning, translocation, and perturbation to one of the parent SMTPs, called "TP2"...
August 22, 2017: Biophysical Journal
#34
JOURNAL ARTICLE
Jing He, Lilia I Melnik, Alexander Komin, Gregory Wiedman, Taylor Fuselier, Cameron F Morris, Charles G Starr, Peter C Searson, William R Gallaher, Kalina Hristova, Robert F Garry, William C Wimley
The Ebola virus (EBOV) genome encodes for a partly conserved, 40-residue, nonstructural polypeptide, called the delta peptide, which is produced in abundance during Ebola virus disease. The function of the delta peptide is unknown, but sequence analysis has suggested that delta peptide could be a viroporin, belonging to a diverse family of membrane-permeabilizing small polypeptides involved in replication and pathogenesis of numerous viruses. Full length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells of rodent, dog, monkey and human origin, increase ion permeability across confluent cell monolayers and permeabilize synthetic lipid bilayers...
May 24, 2017: Journal of Virology
#35
JOURNAL ARTICLE
Gregory Wiedman, Sarah Y Kim, Elmer Zapata-Mercado, William C Wimley, Kalina Hristova
pH-triggered membrane-permeabilizing peptides could be exploited in a variety of applications, such as to enable cargo release from endosomes for cellular delivery, or as cancer therapeutics that selectively permeabilize the plasma membranes of malignant cells. Such peptides would be especially useful if they could enable the movement of macromolecules across membranes, a rare property in membrane-permeabilizing peptides. Here we approach this goal by using an orthogonal high-throughput screen of an iterative peptide library to identify peptide sequences that have the following two properties: (i) little synthetic lipid membrane permeabilization at physiological pH 7 at high peptide concentration and (ii) efficient formation of macromolecule-sized defects in synthetic lipid membranes at acidic pH 5 and low peptide concentration...
January 18, 2017: Journal of the American Chemical Society
#36
JOURNAL ARTICLE
Charles G Starr, Jing He, William C Wimley
Despite longstanding promise and many known examples, antimicrobial peptides (AMPs) have failed, thus far, to impact human medicine. On the basis of the physical chemistry and mechanism of action of AMPs, we hypothesized that host cell interactions could contribute to a loss of activity in vivo where host cells are highly concentrated. To test this idea, we characterized AMP activity in the presence of human red blood cells (RBC). Indeed, we show that most of a representative set of natural and synthetic AMPs tested are significantly inhibited by preincubation with host cells and would be effectively inactive at physiological cell density...
December 16, 2016: ACS Chemical Biology
#37
JOURNAL ARTICLE
Augustine Goba, S Humarr Khan, Mbalu Fonnie, Mohamed Fullah, Alex Moigboi, Alice Kovoma, Vandi Sinnah, Nancy Yoko, Hawa Rogers, Siddiki Safai, Mambu Momoh, Veronica Koroma, Fatima K Kamara, Edwin Konowu, Mohamed Yillah, Issa French, Ibraham Mustapha, Franklyn Kanneh, Momoh Foday, Helena McCarthy, Tiangay Kallon, Mustupha Kallon, Jenneh Naiebu, Josephine Sellu, Abdul A Jalloh, Michael Gbakie, Lansana Kanneh, James L B Massaly, David Kargbo, Brima Kargbo, Mohamed Vandi, Momoh Gbetuwa, Sahr M Gevao, John D Sandi, Simbirie C Jalloh, Donald S Grant, Sylvia O Blyden, Ian Crozier, John S Schieffelin, Susan L McLellan, Shevin T Jacob, Matt L Boisen, Jessica N Hartnett, Robert W Cross, Luis M Branco, Kristian G Andersen, Nathan L Yozwiak, Stephen K Gire, Ridhi Tariyal, Daniel J Park, Allyson M Haislip, Christopher M Bishop, Lilia I Melnik, William R Gallaher, William C Wimley, Jing He, Jeffrey G Shaffer, Brian M Sullivan, Sonia Grillo, Scott Oman, Courtney E Garry, Donna R Edwards, Stephanie J McCormick, Deborah H Elliott, Julie A Rouelle, Chandrika B Kannadka, Ashley A Reyna, Benjamin T Bradley, Haini Yu, Rachael E Yenni, Kathryn M Hastie, Joan B Geisbert, Peter C Kulakosky, Russell B Wilson, Michael B A Oldstone, Kelly R Pitts, Lee A Henderson, James E Robinson, Thomas W Geisbert, Erica Ollmann Saphire, Christian T Happi, Danny A Asogun, Pardis C Sabeti, Robert F Garry
BACKGROUND: Kenema Government Hospital (KGH) has developed an advanced clinical and laboratory research capacity to manage the threat of Lassa fever, a viral hemorrhagic fever (VHF). The 2013-2016 Ebola virus (EBOV) disease (EVD) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of VHFs. METHODS: Because of its proximity to the epicenter of the EVD outbreak, which began in Guinea in March 2014, the KGH Lassa fever Team mobilized to establish EBOV surveillance and diagnostic capabilities...
October 15, 2016: Journal of Infectious Diseases
#38
JOURNAL ARTICLE
Aram J Krauson, O Morgan Hall, Taylor Fuselier, Charles G Starr, W Berkeley Kauffman, William C Wimley
To better understand the sequence-structure-function relationships that control the activity and selectivity of membrane-permeabilizing peptides, we screened a peptide library, based on the archetypal pore-former melittin, for loss-of-function variants. This was accomplished by assaying library members for failure to cause leakage of entrapped contents from synthetic lipid vesicles at a peptide-to-lipid ratio of 1:20, 10-fold higher than the concentration at which melittin efficiently permeabilizes the same vesicles...
December 30, 2015: Journal of the American Chemical Society
#39
REVIEW
W Berkeley Kauffman, Taylor Fuselier, Jing He, William C Wimley
The permeability barrier imposed by cellular membranes limits the access of exogenous compounds to the interior of cells. Researchers and patients alike would benefit from efficient methods for intracellular delivery of a wide range of membrane-impermeant molecules, including biochemically active small molecules, imaging agents, peptides, peptide nucleic acids, proteins, RNA, DNA, and nanoparticles. There has been a sustained effort to exploit cell penetrating peptides (CPPs) for the delivery of such useful cargoes in vitro and in vivo because of their biocompatibility, ease of synthesis, and controllable physical chemistry...
December 2015: Trends in Biochemical Sciences
#40
JOURNAL ARTICLE
William C Wimley
In the study of cell-penetrating and membrane-translocating peptides, a fundamental question occurs as to the contribution arising from fundamental peptide-membrane interactions, relative to the contribution arising from the biology and energy of the cell, mostly occurring in the form of endocytosis and subsequent events. A commonly used approach to begin addressing these mechanistic questions is to measure the degree to which peptides can interact with, and physically disrupt, the integrity of synthetic lipid bilayers...
2015: Methods in Molecular Biology
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