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William wimley

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
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
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
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
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
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
Allison J Farrand, Eileen M Hotze, Takehiro K Sato, Kristin R Wade, William C Wimley, Arthur E Johnson, Rodney K Tweten
The majority of cholesterol-dependent cytolysins (CDCs) utilize cholesterol as a membrane receptor, whereas a small number are restricted to the GPI-anchored protein CD59 for initial membrane recognition. Two cholesterol-binding CDCs, perfringolysin O (PFO) and streptolysin O (SLO), were found to exhibit strikingly different binding properties to cholesterol-rich natural and synthetic membranes. The structural basis for this difference was mapped to one of the loops (L3) in the membrane binding interface that help anchor the toxin monomers to the membrane after receptor (cholesterol) binding by the membrane insertion of its amino acid side chains...
July 17, 2015: Journal of Biological Chemistry
Gregory Wiedman, William C Wimley, Kalina Hristova
In this work, we sought to rationally design membrane-active peptides that are triggered by low pH to form macromolecular-sized pores in lipid bilayers. Such peptides could have broad utility in biotechnology and in nanomedicine as cancer therapeutics or drug delivery vehicles that promote release of macromolecules from endosomes. Our approach to rational design was to combine the properties of a pH-independent peptide, MelP5, which forms large pores allowing passage of macromolecules, with the properties of two pH-dependent membrane-active peptides, pHlip and GALA...
April 2015: Biochimica et Biophysica Acta
Jing He, Charles G Starr, William C Wimley
The rapid rise in morbidity and mortality from drug-resistant pathogenic bacteria has generated elevated interest in combination therapy using antimicrobial agents. Antimicrobial peptides (AMPs) are a candidate drug class to advance the development of combination therapies. Although the literature is ambiguous, the generic membrane disrupting activity of AMPs could enable them to synergize with conventional small molecule antibiotics by increasing access to the cell and by triggering membrane damage mediators...
January 2015: Biochimica et Biophysica Acta
William C Wimley, Kalina Hristova
No abstract text is available yet for this article.
September 2014: Biochimica et Biophysica Acta
Ali Sabahi, Susan L Uprichard, William C Wimley, Srikanta Dash, Robert F Garry
Hepatitis C virus (HCV), a member of the family Flaviviridae, is a leading cause of chronic liver disease and cancer. Recent advances in HCV therapeutics have resulted in improved cure rates, but an HCV vaccine is not available and is urgently needed to control the global pandemic. Vaccine development has been hampered by the lack of high-resolution structural information for the two HCV envelope glycoproteins, E1 and E2. Recently, Kong and coworkers (Science 342:1090-1094, 2013, doi:10.1126/science.1243876) and Khan and coworkers (Nature 509[7500]:381-384, 2014, doi:10...
September 2014: Journal of Virology
Jennifer S Spence, Lilia I Melnik, Hussain Badani, William C Wimley, Robert F Garry
UNLABELLED: The family Arenaviridae includes a number of viruses of public health importance, such as the category A hemorrhagic fever viruses Lassa virus, Junin virus, Machupo virus, Guanarito virus, and Sabia virus. Current chemotherapy for arenavirus infection is limited to the nucleoside analogue ribavirin, which is characterized by considerable toxicity and treatment failure. Using Pichinde virus as a model arenavirus, we attempted to design glycoprotein-derived fusion inhibitors similar to the FDA-approved anti-HIV peptide enfuvirtide...
August 2014: Journal of Virology
Hussain Badani, Robert F Garry, William C Wimley
There are many peptides known that inhibit the entry of enveloped viruses into cells, including one peptide that is successfully being used in the clinic as a drug. In this review, we discuss the discovery, antiviral activity and mechanism of action of such peptides. While peptide entry inhibitors have been discovered by a wide variety of approaches (structure-based, accidental, intentional, rational and brute force) we show here that they share a common physical chemical property: they are at least somewhat hydrophobic and/or amphipathic and have a propensity to interact with membrane interfaces...
September 2014: Biochimica et Biophysica Acta
Gregory Wiedman, Taylor Fuselier, Jing He, Peter C Searson, Kalina Hristova, William C Wimley
Peptides that self-assemble, at low concentration, into bilayer-spanning pores which allow the passage of macromolecules would be beneficial in multiple areas of biotechnology. However, there are few, if any, natural or designed peptides that have this property. Here we show that the 26-residue peptide "MelP5", a synthetically evolved gain-of-function variant of the bee venom lytic peptide melittin identified in a high-throughput screen for small molecule leakage, enables the passage of macromolecules across bilayers under conditions where melittin and other pore-forming peptides do not...
March 26, 2014: Journal of the American Chemical Society
Alexander Kyrychenko, J Alfredo Freites, Jing He, Douglas J Tobias, William C Wimley, Alexey S Ladokhin
We use a number of computational and experimental approaches to investigate the membrane topology of the membrane-interacting C-terminal domain of the HIV-1 gp41 fusion protein. Several putative transmembrane regions are identified using hydrophobicity analysis based on the Wimley-White scales, including the membrane-proximal external region (MPER). The MPER region is an important target for neutralizing anti-HIV monoclonal antibodies and is believed to have an interfacial topology in the membrane. To assess the possibility of a transmembrane topology of MPER, we examined the membrane interactions of a peptide corresponding to a 22-residue stretch of the MPER sequence (residues 662-683) using fluorescence spectroscopy and oriented circular dichroism...
February 4, 2014: Biophysical Journal
Partha K Chandra, Lili Bao, Kyoungsub Song, Fatma M Aboulnasr, Darren P Baker, Nathan Shores, William C Wimley, Shuanghu Liu, Curt H Hagedorn, Serge Y Fuchs, Tong Wu, Luis A Balart, Srikanta Dash
A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors...
January 2014: American Journal of Pathology
Jing He, W Berkeley Kauffman, Taylor Fuselier, Somanna K Naveen, Thomas G Voss, Kalina Hristova, William C Wimley
Direct cellular entry of potentially useful polar compounds into cells is prevented by the hydrophobic barrier of the membrane. Toward circumventing this barrier, we used high throughput screening to identify a family of peptides that carry membrane-impermeant cargos across synthetic membranes. Here we characterize the plasma membrane translocation of these peptides with polar cargos under a variety of conditions. The spontaneous membrane-translocating peptides (SMTPs) delivered the zwitterionic, membrane-impermeant dye tetramethylrhodamine (TAMRA) into cells even when the conditions were not permissive for endocytosis...
October 11, 2013: Journal of Biological Chemistry
Jing He, Aram J Krauson, William C Wimley
We previously performed a lipid vesicle-based, high-throughput screen on a 26-residue combinatorial peptide library that was designed de novo to yield membrane-permeabilizing peptides that fold into β-sheets. The most active and soluble library members that were identified permeabilized lipid vesicles detectably, but not with high potency. Nonetheless, they were broad-spectrum, membrane-permeabilizing antibiotics with minimum sterilizing activity at low µM concentrations. In an expansion of that work, we recently performed an iterative screen in which an active consensus sequence from that first-generation library was used as a template to design a second-generation library which was then screened against lipid vesicles at very high stringency...
January 2014: Biopolymers
Juan Cruz, Mihaela Mihailescu, Greg Wiedman, Katherine Herman, Peter C Searson, William C Wimley, Kalina Hristova
Using a high throughput screen, we have identified a family of 12-residue long peptides that spontaneously translocate across membranes. These peptides function by a poorly understood mechanism that is very different from that of the well-known, highly cationic cell penetrating peptides such as the tat peptide from HIV. The newly discovered translocating peptides can carry polar cargoes across synthetic bilayers and across cellular membranes quickly and spontaneously without disrupting the membrane. Here we report on the biophysical characterization of a representative translocating peptide from the selected family, TP2, as well as a negative control peptide, ONEG, from the same library...
June 4, 2013: Biophysical Journal
William F Walkenhorst, J Wolfgang Klein, Phuong Vo, William C Wimley
We recently described a family of cationic antimicrobial peptides (CAMPs) selected from a combinatorial library that exhibited potent, broad-spectrum activity at neutral pH and low ionic strength. To further delimit the utility and activity profiles of these peptides, we investigated the effects of solution conditions, such as pH and ionic strength, on the efficacy of the peptide antimicrobials against a panel of microorganisms. Peptide minimum sterilizing concentrations (MSCs) varied linearly with pH for each subtype within our family of CAMPs for all organisms tested...
July 2013: Antimicrobial Agents and Chemotherapy
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