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F Brown

Publications and source records attributed to F Brown.

At least 127 records · Page 7Linked to original sources
PubMed1991

Comparison of azabicyclic esters and oxadiazoles as ligands for the muscarinic receptor.

The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents. This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor. Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system. These compounds generally show improved affinity relative to the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine. Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.

Aminoquinolines↗
PubMed1991

Immunological evaluation of the multiple antigen peptide (MAP) system using the major immunogenic site of foot-and-mouth disease virus.

The multiple antigenic peptide (MAP) system for presenting epitopes to the immune system has been studied with an immunogenic foot-and-mouth disease virus (FMDV) peptide comprising amino acids 141-160 of protein VP1. Neutralizing antibody responses known to protect guinea-pigs against challenge infection were obtained with a single inoculation of 0.8-4 micrograms of peptide, presented as an octamer or a tetramer, whereas 20 micrograms of a dimer were required to evoke a similar level of antibody. A monomeric preparation did not elicit measurable levels of neutralizing antibody at doses up to 20 micrograms. The octameric MAP was also immunogenic using an aluminum hydroxide adjuvant. Antibodies elicited by the octameric, tetrameric and dimeric constructs differed qualitatively in their reaction with sequences within the 141-160 peptide. Those against the octamer reacted poorly with peptides within the 141-160 sequence, whereas those elicited by the tetramer and dimer reacted preferentially with the peptides covering the N-terminal region. The levels of neutralizing antibody obtained with the octamer and tetramer compare favourably with those obtained when the FMDV peptide is attached to carrier proteins but are lower than those obtained when it is presented as part of a peptide-hepatitis B virus core particle. Nevertheless, the ability to elicit protective levels of neutralizing antibody without the use of a carrier protein would be a distinct advantage in the development of synthetic peptide vaccines.

Adjuvants, Immunologic↗
PubMed1991

An overview of the inactivation of FMDV and the implications when residual virus is present in vaccines.

Most foot-and-mouth disease (FMD) vaccines are prepared by inactivating the virus with acetylethyleneimine or binary ethyleneimine. However, formaldehyde is still used by some manufacturers despite the well-documented evidence that inactivation with this reagent is not a linear or first-order reaction. Recent German work provides clear evidence that almost all the outbreaks in Western Europe in recent years have been caused by viruses closely related to strains which were isolated more than 20 years ago and are used for the production of vaccines. Moreover, with one exception, all the vaccines connected with the outbreaks were prepared by formaldehyde inactivation. The implications of these outbreaks are both immediate and longer term. The immediate effect is that they severely disrupt trading in meat and dairy products. The longer term effect has been the decision to abandon vaccination in Western Europe. This could have serious implications as trading with Eastern European countries will be expected to increase in the immediate future.

Animals↗
PubMed1991

A CD strategy for the study of polypeptide folding/unfolding. A synthetic foot-and-mouth disease virus immunogenic peptide.

The circular dichroism spectrum of the 20-residue immunogenic peptide from the foot-and-mouth disease virus (VP1; 141-160 of serotype A, subtype 12) was solvent- and temperature-dependent. Careful solvent titration revealed two isodichroic points and plateaux consistent with stepwise unfolding of specific stable conformations. Variable temperature studies in cryogenic solvents and urea perturbation were consistent with the existence of three conformational moieties, the left-handed extended helix, the alpha-helix, and the 3(10) helix. The number of residues in each helix was confirmed by CD spectral simulations. The strategy described here can be used to determine the components of a conformational equilibrium and their statistical weights, to study peptide folding and unfolding and to determine the bioactive conformation(s) of linear peptides. The conclusions were supported by 2D-NMR studies. A new mechanism for the stabilization of left-handed extended helices and destabilization of alpha-helices by urea is proposed. The structure of the peptide as resolved by CD spectroscopy is of particular significance since the conformation of this antigenic sequence in situ has so far not been solved by X-ray crystallography.

Amino Acid Sequence↗
PubMed1990

Structural and serological evidence for a novel mechanism of antigenic variation in foot-and-mouth disease virus.

Changes resulting in altered antigenic properties of viruses nearly always occur on their surface and have been attributed to the substitution of residues directly involved in binding antibody. To investigate the mechanism of antigenic variation in foot-and-mouth disease virus (FMDV), variants that escape neutralization by a monoclonal antibody have been compared crystallographically and serologically with parental virus. FMDVs form one of the four genera of the Picornaviridae. The unenveloped icosahedral shell comprises 60 copies each of four structural proteins VP1-4. Representatives from each of the genera have similar overall structure, but differences in the external features. For example, human rhinovirus has a pronounced 'canyon' that is proposed to contain the cell attachment site, whereas elements of the attachment site for FMDV, which involves the G-H loop (residues 134-160) and C-terminus (200-213) of VP1, are exposed on the surface. Moreover, this G-H loop, which is a major antigenic site of FMDV, forms a prominent, highly accessible protrusion, a feature not seen in other picornaviruses. It is this loop that is perturbed in the variant viruses that we have studied. The amino acid mutations characterizing the variants are not at positions directly involved in antibody binding, but result in far-reaching perturbations of the surface structure of the virus. Thus, this virus seems to use a novel escape mechanism whereby an induced conformational change in a major antigenic loop destroys the integrity of the epitope.

Antibodies, Monoclonal↗
PubMed1990

Synthetic peptides as potential vaccines against foot-and-mouth disease.

Advances made in our knowledge of the structure of foot-and-mouth disease virus have enabled us to identify a fragment, consisting of 20 amino acids, of one of the four proteins of the particle, which elicits neutralizing antibodies in experimental animals and in cattle and pigs. The fragment has been synthesised chemically by Merrifield's solid phase method and biochemically as part of different fusion proteins. The level of the immune response to the peptide, which depends critically on the way it is presented, affords protection against experimental challenge and holds out promise for its future as a vaccine.

Amino Acid Sequence↗
PubMed1990

"Instant-mix" whole brain photon with neutron boost radiotherapy for malignant gliomas.

From July 1985 through March 1987, 44 consecutive patients with supratentorial, nonmetastatic anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with whole brain photon irradiation with concomitant neutron boost at the University of Chicago. All patients had biopsy proven disease and surgery ranged from biopsy to total gross excision. Whole brain photon radiation was given at 1.5 Gy per fraction, 5 days weekly for a total dose of 45 Gy in 6 weeks. Neutron boost radiation was prescribed to a target minimum dose that included the pre-surgical CT tumor volume plus 1 cm margin. Neutrons were administered 5-20 minutes prior to photon radiation twice weekly and a total dose of 5.2 Gyn gamma was administered over 6 weeks. Median follow-up was 36 months. The median survival was 40.3 months for anaplastic astrocytoma (10 patients) and 11 months for glioblastoma multiforme (34 patients) and 12 months for the overall group. Variables that predicted longer median survival included histology (AA vs. GBM), age (less than or equal to 39 years vs. older), and extent of surgery (total gross or partial excision vs. biopsy) whereas tumor size and Karnofsky performance status did not have a significant influence. The median survival of the anaplastic astrocytoma group was better than expected compared to the RTOG 80-07 study (a dose-finding study of similar design to this study) and historical data. Reasons for this are discussed.

Adult↗
PubMed1990

The structure of foot-and-mouth disease virus: implications for its physical and biological properties.

The structure of foot-and-mouth disease virus has been solved at a resolution of 2.9 A by X-ray diffraction techniques. The overall structural organisation of the particle is similar to that seen in other picornaviruses but there are several unique features. Many of these help to explain its characteristic physical and biological properties. In particular the canyon or pit found at the surface of other picornaviruses is lacking, which has important implications for cell attachment and the process of infection. Also there are 60 large disordered protrusions at the surface corresponding to the major antigenic site. This disorder is of particular interest in relation to the striking ability of linear synthetic peptides to induce protective immunity against foot-and-mouth disease.

Animals↗
PubMed1990

Expression in yeast of amino-terminal peptide fusions to hepatitis B core antigen and their immunological properties.

Hepatitis B core protein (HBcAg) is a potent antigen that gives both a T-cell-dependent and a T-cell-independent antibody response. It has been shown that a foreign epitope can be fused to the amino terminus of HBcAg without affecting particle integrity, and that the resulting chimaeric cores retain the immunogenicity of the foreign epitope. Here we describe the efficient expression in yeast of two different chimaeric cores, carrying epitopes of Foot and Mouth Disease Virus (FMDV) or human chorionic gonadotrophin (hCG), which are candidates for FMD and contraceptive vaccines, respectively. These cores could not be produced in E. coli in soluble form but were expressed to high levels in yeast. We constructed a yeast expression vector that allows rapid production of different chimaeric cores by cloning in cassettes encoding foreign epitopes. Both FMDV and hCG-cores were shown to present the epitopes at the surface of the particles. The FMDV-cores produced in yeast were efficient inducers of neutralising antibodies in guinea-pigs after one low dose.

Amino Acid Sequence↗
PubMed1990

Immunological properties of hepatitis B core antigen fusion proteins.

The immunogenicity of a 19 amino acid peptide from foot-and-mouth disease virus has previously been shown to approach that of the inactivated virus from which it was derived after multimeric particulate presentation as an N-terminal fusion with hepatitis B core antigen. In this report we demonstrate that rhinovirus peptide-hepatitis B core antigen fusion proteins are 10-fold more immunogenic than peptide coupled to keyhole limpet hemocyanin and 100-fold more immunogenic than uncoupled peptide with an added helper T-cell epitope. The fusion proteins can be readily administered without adjuvant or with adjuvants acceptable for human and veterinary application and can elicit a response after nasal or oral dosing. The fusion proteins can also act as T-cell-independent antigens. These properties provide further support for their suitability as presentation systems for "foreign" epitopes in the development of vaccines.

Adjuvants, Immunologic↗
PubMed1990

Chemically synthesized peptides elicit neutralizing antibody to bovine enterovirus.

Synthetic peptides representing 14 regions of the bovine enterovirus structural proteins were used to raise antibodies in mice. The peptides were predicted using amino acid sequence alignments with the position of antigenic sites on other picornaviruses. Five of the anti-peptide antibodies reacted with the virus in an immunoprecipitation test. Furthermore, each of these anti-peptide antibodies neutralized virus infectivity; those directed against peptides of VP2 and VP3 neutralized to a greater extent than those directed against peptides of VP1. The positions of these epitopes in the viral structural proteins are discussed in relation to corresponding positions in other picornaviruses.

Amino Acid Sequence↗
PubMed1990

Presentation and immunogenicity of viral epitopes on the surface of hybrid hepatitis B virus core particles produced in bacteria.

We recently reported the enhanced immunogenicity of a peptide epitope when it was presented as a fusion protein with hepatitis B core antigen. In those experiments the fusion protein was expressed in vaccinia virus. We have now refined the system so that large amounts of highly immunogenic particles can be produced using a simple bacterial expression system. We describe the expression of three different viral epitopes as chimeric particles that induce good antibody responses to each epitope after one dose of low amounts of antigen. Finally we demonstrate that the immunogenicity is a reflection of both T helper cell sites within the core protein and also the particulate nature of the immunogens.

Amino Acid Sequence↗
PubMed1990

New approaches in viral vaccine development.

With the exception of the vaccine against hepatitis B the principles involved in the production of the viral vaccines in use today have not changed since Jenner (1) first developed the vaccine which was so important in the control and eventual eradication of smallpox in 1977. All have relied on the presentation of the live attenuated or inactivated virus to the host, either orally or by injection, so that it elicited the formation of antibody and primed memory cells for a rapid response to the subsequent invasion of the virus. With the discovery that protective immunity could be obtained with isolated individual proteins from virus particles and the development of methods for the expression of these proteins, both in vivo and in vitro, there is now considerable promise that immunity can be induced without the need to use the disease agent itself. Moreover, the molecular basis of the immune response is now beginning to be understood, thus allowing a more rational approach to the design of vaccines for individual diseases.

Administration, Oral↗
PubMed1990

Neutralizing antibodies to all seven serotypes of foot-and-mouth disease virus elicited by synthetic peptides.

Uncoupled peptides from all seven serotypes of foot-and-mouth disease virus (FMDV) protein VP1 have been used to elicit neutralizing antibody responses in guinea-pigs. The responses were largely serotype specific, although some significant cross-neutralization was observed. Dimeric tandem peptides have also been used to simultaneously elicit neutralizing antibodies to two different FMDV serotypes. The possible existence of structural features common to the B-cell neutralization sites or the guinea-pig helper T-cell sites within all seven peptides are analysed and discussed.

Amino Acid Sequence↗
PubMed1989

The three-dimensional structure of foot-and-mouth disease virus at 2.9 A resolution.

The structure of foot-and-mouth disease virus has been determined at close to atomic resolution by X-ray diffraction without experimental phase information. The virus shows similarities with other picornaviruses but also several unique features. The canyon or pit found in other picornaviruses is absent; this has important implications for cell attachment. The most immunogenic portion of the capsid, which acts as a potent peptide vaccine, forms a disordered protrusion on the virus surface.

Algorithms↗
PubMed1989

Helper T-cell determinants in vaccine design.

Mice belonging to the H-2d haplotype do not respond to the 141-160 peptide of foot-and-mouth disease virus protein VP1. However, when defined 'foreign' helper T-cell determinants from ovalbumin or sperm whale myoglobin are added they do respond. These observations are likely to have important implications for the design of peptide vaccines.

Animals↗
PubMed1989

Vaccination.

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Acquired Immunodeficiency Syndrome↗