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Design strategies for anti-amyloid agentsJody M MasonÃ, Nicoleta KokkoniÃ, Kelvin Stotty and Andrew J DoigÃyz Numerous diseases have been linked to a common pathogenic example, a 37-residue peptide called islet amyloid poly- process called amyloidosis, whereby proteins or peptides clump peptide (IAPP, also known as amylin) aggregates to form together in the brain or body to form toxic soluble oligomers and/ insoluble amyloid fibres in the islet cells of the pancreas, or insoluble fibres. An attractive strategy to develop therapies for which contain the b cells that produce insulin The these diseases is therefore to inhibit or reverse protein/peptide role of amyloidosis in AD has been a topic of intense aggregation. A diverse range of small organic ligands have been debate because the distribution of amyloid plaque in the found to act as aggregation inhibitors. Alternatively, the wild-type brain tends to correlate rather poorly with the specific peptide can be derivatised so that it still binds to the amyloid regions of the brain that are actually affected by the target, but prevents further aggregation. This can be achieved by disease, leading some to believe that amyloid plaques adding a bulky group or charged amino acid to either end of the might simply form as a downstream effect of the disease peptide, or by incorporating proline residues or N-methylated or may even help to protect against the real cause of the disease, rather than actually cause it . A resolution tothese anomalies may be that the soluble oligomeric form of the amyloid is the principal pathogenic form, rather ÃDepartment of Biomolecular Sciences, UMIST, PO Box 88, Manchester M60 1QD, UKySenexis Limited, Department of Biomolecular Sciences, UMIST, Alternative strategies to treat amyloidosis PO Box 88, Manchester M60 1QD, UKze-mail: Numerous groups are developing treatments designedto block various key steps in the amyloidosis process.
Specific therapeutic strategies currently being pursued Current Opinion in Structural Biology 2003, 13:1–7 1. Inhibiting expression of the amyloidogenic protein or stabilizing its native form using small organic ligands.
Edited by Sophie E Jackson and Lynne Regan 2. Inhibiting release of the amyloidogenic peptide from its parent protein using protease inhibitors.
ß 2003 Elsevier Ltd. All rights reserved.
3. Inhibiting aggregation of the protein or peptide directly using small ligands or indirectly by vaccination.
4. Inhibiting other effects of the disease that may or may not be directly associated with amyloidosis (e.g.
inflammation and oxidative stress) — replacing cells that have been killed by the disease (e.g. by cell or gene therapy) and alleviating the symptoms of the disease, but without necessarily blocking the patho- The most effective treatments may be those designed toinhibit steps that precede protein/peptide aggregation, by blocking production of the amyloidogenic protein or Alzheimer’s disease (AD) has long been associated with peptide in the first place. However, this requires blocking the accumulation of insoluble amyloid ‘plaques’ in the the expression or activity of a natural protein or peptide brain. These plaques form by a process called amyloid- that has presumably evolved to perform some other, osis, whereby a 40- to 43-residue peptide called b-amyloid important biological function in vivo. For example, many (Ab) aggregates into insoluble fibres. Many other neuro- large pharma companies are currently developing inhibi- degenerative diseases have been associated with the tors of b- or g-secretase as potential drugs for AD. These aggregation of specific proteins or peptides in various two enzymes cleave amyloid precursor protein to produce parts of the brain, including a-synuclein in Parkinson’s the Ab peptide associated with the disease, but they have disease, huntingtin in Huntington’s disease, prions in the also been shown to perform other, important biological spongiform encephalopathies and transthyretin (TTR) in functions so it may not be possible to identify any transthyretin amyloidosis . Furthermore, several non- inhibitors of these enzymes that are safe enough for use as neurodegenerative ageing-related diseases have been drugs in vivo. Moreover, this strategy is inapplicable to associated with the aggregation of specific proteins or Parkinson’s disease, Huntington’s disease, Creutzfeldt– peptides in other parts of the body. In type II diabetes, for Jakob disease and type II diabetes, for which it is the Current Opinion in Structural Biology 2003, 13:1–7 Alternative therapeutic strategies to block amyloidosis.
full-length protein or peptide that aggregates, rather than stabilizing the monomeric native state, hence increasing an intermediate within the protein degradation pathway.
the kinetic barrier associated with misfolding On the other hand, treatments designed to target steps Congo red (CR) is a hydrophilic symmetrical sulfonated that follow protein/peptide aggregation are less likely to azodye that binds specifically to amyloid fibrils in an as yet be effective because they would not prevent the forma- unidentified manner. Studies on CR binding have sug- tion of toxic soluble oligomers or insoluble fibres, which gested that it can inhibit Ab aggregation in AD could continue to kill cells. Thus, an attractive therapeu- Sanchez et al. showed that CR was also able to tic strategy in principle is to inhibit and preferably reverse promote the clearance of expanded polyglutamine protein/peptide aggregation itself, because this appears to (polyQ)-containing aggregates (present in Huntington’s be the first step in the pathogenic process of amyloidosis disease) both in vivo and in vitro. Several derivatives of () that is not associated with some natural bio- CR, as well as thioflavin S, chrysamine G and direct fast logical function . In this review, we discuss a range of yellow, are also effective inhibitors of huntingtin protein molecules recently found to inhibit aggregation. Most work in this field has focused on Ab, although a widerrange of targets have been addressed in recent years.
A great number of diverse organic compounds havebeen found to inhibit or reduce the aggregation of Ab into fibrils in vitro. These include nicotine (some rare A vast range of diverse molecules have been studied as good news for smokers) b-cyclodextrin hemin potential inhibitors of amyloid formation. Here, we dis- and related porphyrins , anthracycline 40-iodo-40- cuss some of these, illustrating the types of compound deoxydoxorubicin , hexadecyl-N-methylpiperidi- nium (HMP) bromide rifampicin , (À)-5,8-dihy-droxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahy- Tetrameric TTR, involved in thyroxine transport, can dronapthalene and melatonin Salvianolic acid B form amyloid fibrils, leading to TTR amyloidosis. Using also reduces PC-12 cellular toxicity of aged Ab mass spectrometric methods, McCammon et al. Kiuchi et al. tested type IV collagen, a molecule that found 18 ligands (N-phenyl phenoxazines and flufenamic localises in senile plaques of AD patients, as a potential acid derivatives) that function as inhibitors of amyloid inhibitor of amyloid. Thioflavin T fluorescence and formation through their ability to stabilize the tetrameric electron microscopy studies demonstrated that collagen structure of human wild-type TTR and amyloidogenic IV inhibited Ab(1–40) fibril formation. Bartolini et al. TTR variants V30M and L55P. Another series of TTR induced Ab aggregation using human recombinant ace- amyloidosis inhibitors has been studied that function by tylcholinesterase and small molecules were tested for Current Opinion in Structural Biology 2003, 13:1–7 Free peptides associate asextended β strands with twosticky edges to form β sheet Mechanism of peptide aggregation in amyloidosis.
their ability to inhibit the aggregation of Ab. Molecules more, McLaurin et al. showed that immunisation such as propidium, a peripheral anionic site ligand, with protofibrillar forms of Ab(1–42) induced therapeuti- decamethonium, donepezil and physostigmine were cally effective IgG2b antibodies that recognize Ab(4–10) found to inhibit Ab peptide aggregation. Propidium, and inhibit Ab protofibril aggregation and toxicity.
decamethonium and physostigmine are known as ace- The antibody 1C2, which recognizes elongated polyQ tylcholinesterase inhibitors, whereas donepezil is a drug chains, was also effective in inhibiting huntingtin protein already used by AD patients. Nonsteroidal anti-inflam- matory drugs (NSAIDs) and aspirin have also beenreported to inhibit human aluminium-induced Ab and shows examples of some of these Ab inhibitors.
amylin aggregation in vitro . More recently, Kim and Their lack of structural similarity is striking, suggesting Lee found 1,2-(dimethoxymethano)fullerene was that they bind to different sites within amyloid, a able to bind specifically to the 16–20 region of Ab pep- situation in contrast to most drugs, which bind to a tides with high affinity, thus inhibiting amyloid aggrega- single active site. This makes inferring conclusions from structure/activity relationships, and hence rational drugdesign, difficult.
Copper and iron are present in Ab deposits and induce theproduction of hydrogen peroxide, which may mediate Rational design of peptide-based inhibitors oxidative damage to the brain in AD Bush developed metal-binding compounds that inhibit the in An attractive strategy to develop amyloid aggregation vitro generation of hydrogen peroxide by Ab. These inhibitors is to start with the wild-type peptide as a lead, compounds are also able to reverse the aggregation of as it is already known to bind to itself The first Ab in vitro and from human brain post-mortem speci- group to make use of a core section of Ab as a potential mens. One of the compounds, clioquinol (CQ), a copper/ drug lead was Tjernberg and co-workers who zinc chelator, was given orally to APP2576 transgenic showed that Ab(16–20) is able to bind full-length Ab mice and induced a 49% decrease in brain Ab deposition.
and thus prevent its assembly into fibrils. Using moleculargraphics simulations, they hypothesized that it bound Immunisation of AD mouse models with Ab significantly stereospecifically and in an antiparallel conformation to reduces both the density of cerebral amyloid plaques and Ab Despite being shown to form fibrils in isolation, the degree of cognitive impairment Further- Ab(16–20) was proposed to be a key region from which Current Opinion in Structural Biology 2003, 13:1–7 Examples of ‘small-molecule’ peptide aggregation inhibitors. HMP, hexadecyl-N-methylpiperidinium.
a lead compound could be created against amyloid.
protein 114–122 as a template, Soto has also produced Ligands based on Ab(16–20) and composed entirely of proline-containing b-sheet breaker peptides with the D-amino acids were comparable to all-L ligands in their ability to prevent the conformational change of the prion ability to prevent fibril formation, with the additional Based initially on the 15–25 region of Ab, Murphy and co- Soto et al. also began work on inhibitors based on the workers designed a peptide with a ‘recognition core region of Ab, in this case residues 17–21. The element’ homologous to Ab, but with a ‘disrupting strategy is based upon substituting key residues for element’, tagged to the C terminus, designed to interfere prolines in a bid to reduce the b-propensity of the peptide with Ab aggregation (Having shown that at while retaining its hydrophobicity. In this way, the pro- least three lysines are required as an appropriate disrupt- line-containing Ab(17–21) region may bind to aggregated ing element, the compound (KLVFFKKKK) showed Ab and prevent further fibril growth (). A lead considerable promise, as it accelerated Ab aggregation eleven amino acid inhibitor was reduced to five amino kinetics, altered fibril morphology and reduced toxicity in acids with greater ability to prevent fibril formation. All-D MTT assays using PC-12 cells. The anionic disrupting analogues were again found to be as effective as all-L, compound KLVFFEEEE had similar effects, whereas but with increased protease resistance. These so-called the neutral disrupting compound KLVFFSSSS was inef- b-sheet breaker peptides were shown not only to be stable fective, suggesting that the charged nature of the dis- in vivo, but also to be small and hydrophobic enough to rupting element is critical. These results were interesting have blood-brain barrier permeability Using prion because they implied that Ab aggregation need not be Current Opinion in Structural Biology 2003, 13:1–7 Inhibition of amyloidosis by synthetic peptide derivatives. (i) Proline introduced as b-sheet breaker. (ii) Terminal blocking group [e.g. cholyl or poly(lys)].
(iii) N-methylated amides to block one edge of b strand.
blocked to prevent toxicity and that the compounds ‘core domain’ region. These peptides can prevent Ab perhaps work by accelerating aggregation to remove toxic fibrils from forming and break down preformed fibrils.
soluble oligomers, or ‘protofibrils’.
They have the added advantages of high proteolytic resis-tance, solubility, blood-brain barrier permeability Findeis et al. analysed many truncated variants of Ab and propensity to form b-structure at the N-methylated with a variety of different N-terminal modifications to site. Kapurniotu et al. employed the same strategy establish a small yet effective inhibitor of Ab polymerisa- against a region within residues 20–27 of IAPP. The use tion. Their strategy was to retain a peptide that could bind of larger substituents than a methyl to block hydrogen to Ab and had a bulky group, such as a steroid, at its terminus to hinder further Ab association (Theall-D-amino acid peptide cholyl-LVFFA-OH was a potent inhibitor of Ab polymerisation, but was all but cleared Although it is not yet certain whether preventing amyloid upon hepatic first pass, possibly because the cholyl group proteins from aggregating will be therapeutically benefi- was recognised as an endogenous bile component cial, numerous anti-amyloidogenic compounds have beendeveloped. Such compounds can be discovered either Several groups are studying the incorporation of N-methyl by screening large libraries, derivatising a lead known amino acids into peptides as inhibitors of amyloidosis.
to bind to amyloid, or by modifying core regions of the These peptides again correspond to a region that is key to amyloidogenic peptide or protein. The common fibrillar the amyloid protein. One side presents a hydrogen-bond- structure adopted by diverse peptides and the success of ing ‘complementary’ face to the protein, with the other general methods to produce inhibitors (offer the having N-methyl groups in place of backbone NH groups, exciting possibility that a family of compounds may be thus presenting a ‘blocking’ face (Hughes et al.
produced to act as therapeutic molecules for a range of have shown that N-methyl derivatives of Ab(25–35) are able to prevent aggregation and inhibit toxicity inPC-12 cells. Meredith and co-workers investigated N-methylated peptides of a region corresponding to resi- We thank the Biotechnology and Biological Science Research Council (grant dues 16–22 and subsequently 16–20 of the amyloid number 36/C14685) and the AG Leventis Foundation for funding.
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Current Opinion in Structural Biology 2003, 13:1–7



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Microsoft word - mc - eating right for mum - karen wright

HEALTHY MUM HAPPY BABY Being healthy may be the last thing on your mind as you adapt to the juggling act of life with a new baby. However, being a good Mum means looking after yourself as well as your little one, and this includes eating a well balanced diet. Eating the right food now will give you the experience and knowledge of what’s best for your baby at that all important weanin

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