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: andrew.doig@umist.ac.uk
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.
Current Opinion in Structural Biology 2003, 13:1–7
implications for Huntington’s disease therapy. Proc Natl AcadSci USA 2000, 97:6739-6744.
Papers of particular interest, published within the annual period ofreview, have been highlighted as:
18. Salomon AR, Marcinowski KJ, Friedland RP, Zagorski MG:
Nicotine inhibits amyloid formation by the b-peptide.
19. Camilleri P, Haskins NJ, Howlett DR: b-Cyclodextrin interacts
Dobson CM: Protein misfolding, evolution and disease.
with the Alzheimer amyloid b-A4 peptide. FEBS Lett 1994,
Trends Biochem Sci 1999, 24:329-332.
Murphy RM: Peptide aggregation in neurodegenerative
20. Howlett D, Cutler P, Heales S, Camilleri P: Hemin and related
disease. Annu Rev Biomed Eng 2002, 4:155-174.
porphyrins inhibit b-amyloid aggregation. FEBS Lett 1997,417:249-251.
Clark A, Lewis CE, Willis AC, Cooper GJS, Morris JF, Reid KBM,Turner RC: Islet amyloid formed from diabetes-associated
21. Merlini G, Ascari E, Amboldi N, Belloti V, Arbustini E, Perfetti V,
peptide may be pathogenic in type II diabetes. Lancet 1987,
Ferrari M, Zorzoli I, Marinone MG, Garini P: Interaction of the
anthracycline 4(-iodo-4(-deoxydoxorubicin with amyloidfibrils: inhibition of amyloidogenesis. Proc Natl Acad Sci USA
Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G,
Smith MA: Copernicus revisited: amyloid b in Alzheimer’sdisease. Neurobiol Aging 2001, 22:131-146.
22. Wood SJ, MacKenzie L, Maleef B, Hurle MR, Wetzel R:
Selective inhibition of Ab fibril formation. J Biol Chem 1996,
Robinson S, Bishop G: Ab as a bioflocculant: implications for the
amyloid hypothesis of Alzheimer’s disease. Neurobiol Aging2002, 23:1051-1072.
23. Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H,
Endo N: Inhibition of amyloid b protein aggregation and
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos
neurotoxicity by rifampicin. Its possible function as a hydroxyl
M, Morgan TE, Rozovsky I, Trommer B, Viola KL et al.: Diffusible,
radical scavenger. J Biol Chem 1996, 271:6839-6844.
nonfibrillar ligands derived from Abeta1-42 are potent centralnervous system neurotoxins. Proc Natl Acad Sci USA 1998,
24. Parker MH, Chen R, Conway KA, Lee DH, Luo C, Boyd RE, Nortey
SO, Ross TM, Scott MK, Reitz AB: Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene:
Klein WL, Krafft GA, Finch CE: Targeting small A beta oligomers:
an inhibitor of b-amyloid(1-42) aggregation. Bioorg Med Chem
the solution to an Alzheimer’s disease conundrum?
25. Pappola M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M,
De Felice FG, Ferreira ST: b-amyloid production, aggregation,
Frangione B, Ghiso J: Inhibition of Alzheimer b-fibrillogenesis by
and clearance as targets for therapy in Alzheimer’s disease.
melatonin. J Biol Chem 1998, 273:7185-7188.
Cell Mol Neurobiol 2002, 22:545-563.
26. Tang NK, Zhang JT: Salvianolic acid B inhibits fibril formation
Conway KA, Baxter EW, Felsenstein KM, Reitz AB: Emerging
and neurotoxicity of amyloid b-protein in vitro. Acta Pharmacol
b-amyloid therapies for the treatment of Alzheimer’s disease.
27. Kiuchi Y, Isobe Y, Fukushima K: Type IV collagen prevents
10. Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E,
amyloid b-protein fibril formation. Life Sci 2002, 70:1555-1564.
Schneider LS: A critical analysis of new molecular targets andstrategies for drug developments in Alzheimer’s disease.
28. Bartolini M, Bertucci C, Cavrini V, Andrisano V: b-Amyloid
aggregation induced by human acetylcholinesterase: inhibitionstudies. Biochem Pharmacol 2003, 65:407-416.
11. Haass C, De Strooper B: The presenilins in Alzheimer’s disease
— Proteolysis holds the key. Science 1999, 286:916-919.
29. Thomas T, Nadackal GT, Thomas K: Aspirin and diabetes:
inhibition of amylin aggregation by nonsteroidal anti-
12. Lansbury PTJ: Inhibition of amyloid formation: a strategy to
inflammatory drugs. Exp Clin Endocrinol Diabetes 2003, 111:8-11.
delay the onset of Alzheimer’s disease. Curr Opin Chem Biol1997, 1:260-267.
30. Kim JE, Lee M: Fullerene inhibits b-amyloid peptide
aggregation. Biochem Biophys Res Comm 2003, 303:576-579.
13. McCammon MG, Scott DJ, Keetch CA, Greene LH, Purkey HE,
Petrassi HM, Kelly JW, Robinson CV: Screening transthyretin
31. Varadarajan S, Yatin S, Aksenova M, Butterfield DA: Alzheimer’s
amyloid fibril inhibitors: characterization of novel multiprotein,
amyloid b-peptide-associated free radical oxidative stress and
multiligand complexes by mass spectrometry. Structure 2002,
neurotoxicity. J Struct Biol 2000, 130:184-208.
32. Bush AI: Metal complexing agents as therapies for Alzheimer’s
14. Hammarstrom P, Wiseman RL, Powers ET, Kelly JW: Prevention of
disease. Neurobiol Aging 2002, 23:1031-1038.
transthyretin amyloid disease by changing protein misfoldingenergetics. Science 2003, 299:713-716.
33. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt
TTR forms amyloid via a tetramer. Kelly and co-workers demonstrate the
SD, Chishti MA, Horne P, Heslin D, French J et al.: Ab peptide
strategy of stabilizing the monomeric form by small-molecule binding,
immunization reduces behavioural impairment and plaques in
thus lowering the tetramer concentration.
a model of Alzheimer’s disease. Nature 2000, 408:979-982.
15. Burgevin MC, Passat M, Daniel N, Capet M, Doble A: Congo red
34. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C,
protects against toxicity of b-amyloid peptides on rat
Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D et al.: Ab peptide
hippocampal neurones. Neuroreport 1994, 5:2429-2432.
vaccination prevents memory loss in an animal model ofAlzheimer’s disease. Nature 2000, 408:982-985.
16. Sanchez I, Mahlke C, Yuan J: Pivotal role of oligomerization in
expanded polyglutamine neurodegenerative disorders.
35. Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T,
Hu K, Huang J, Johnson-Wood K, Khan K et al.: Immunization with
Congo red, a molecule that had already been shown to inhibit Ab amyloid
amyloid-b attenuates Alzheimer-disease-like pathology in the
formation in vitro, was able to promote the clearance of expanded polyQ-
PDAPP mouse. Nature 1999, 400:173-177.
containing aggregates (present in huntingtin) in vitro and also in vivo. Thiswork has shown that small anti-amyloid molecules can act in vivo and
36. McLaurin J, Cecal R, Kierstead ME, Tian X, Phinney AL, Manea M,
therefore have the potential to act as therapeutic drugs in amyloidogenic
French JE, Lambermon MH, Darabie AA, Brown ME et al.:
Therapeutically effective antibodies against amyloid-b peptidetarget amyloid-b residues 4-10 and inhibit cytotoxicity and
17. Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R,
fibrillogenesis. Nat Med 2002, 8:1263-1269.
Schugardt N, Lehrach H, Wanker EE: Inhibition of huntingtin
In this study, antibodies directed against residues 4–10 in Ab(1–42) inhibit
fibrillogenesis by specific antibodies and small molecules:
Ab fibrillogenesis and cytotoxicity without eliciting an inflammatory
Current Opinion in Structural Biology 2003, 13:1–7
response. These findings are of great interest as they provide the basis for
45. Lowe TL, Strzelec A, Kiessling LL, Murphy RM: Structure-function
improved immunisation antigens, as well as attempts to design small-
relationships for inhibitors of b-amyloid toxicity containing the
molecule mimics as alternative therapies.
recognition sequence KLVFF. Biochemistry 2001, 40:7882-7889.
37. Tjernberg LO, Na¨slund J, Lindqvist F, Johansson J, Karlstro¨m AR,
46. Findeis MA, Musso GM, Arico-Muendel CC, Benjamin HW, Hundal
Thyberg J, Terenius L, Nordstedt C: Arrest of b-amyloid fibril
AM, Lee J-J, Chin J, Kelley M, Wakefield J, Hayward NJ, Molineaux
formation by a pentapeptide ligand. J Biol Chem 1996,
SM: Modified-peptide inhibitors of amyloid b-peptide
polymerization. Biochemistry 1999, 38:6791-6800.
38. Tjernberg LO, Lilliehook C, Callaway DJE, Naslund J, Hahne S,
47. Hughes E, Burke RM, Doig AJ: Inhibition of toxicity in b-amyloid
Thyberg J, Terenius L, Nordstedt C: Controlling amyloid
peptide fragment b(25-35) using N-methylated derivatives — a
b-peptide fibril formation with protease-stable ligands.
general strategy to prevent amyloid formation. J Biol Chem
N-methylation of an amyloidogenic peptide gives Ab aggregation
39. Soto C, Kindy MS, Baumann M, Frangione B: Inhibition of
Alzheimer’s amyloidosis by peptides that prevent b-sheetconformation. Biochem Biophys Res Commun 1996,
48. Gordon DJ, Sciaretta KL, Meredith SC: Inhibition of b-amyloid(40)
fibrillogenesis and disassembly of b-amyloid(40) fibrils by shortb-amyloid cogeners containing N-methyl amino acids at
40. Poduslo JF, Curran GL, Kumar A, Frangione B, Soto C: b-Sheet
alternate residues. Biochemistry 2001, 40:8237-8245.
breaker peptide inhibitor of Alzheimer’s amyloidogenesis withincreased blood-brain barrier permeability and resistance to
49. Gordon DJ, Tappe R, Meredith SC: Design and characterization
proteolytic degradation in plasma. J Neurobiol 1999, 39:371-382.
of a membrane permeable N-methyl amino acid-containingpeptide that inhibits Ab(1-40) fibrillogenesis. J Pept Res 2002,
41. Soto C, Sigurdsson EM, Morelli L, Kumar RA, Castan˜o EM,
Frangione B: b-Sheet breaker peptides inhibit fibrillogenesis in arat brain model of amyloidosis: implications for Alzheimer’s
50. Adessi C, Frossard M-J, Boissard C, Fraga S, Bieler S, Ruckle T,
Vilbois F, Robinson SM, Mutter M, Banks WA, Soto C:Pharmacological profiles of peptide drug candidates for the
42. Soto C: Alzheimer’s and prion disease as disorders of protein
treatment of Alzheimer’s disease. J Biol Chem 2003,
conformation: implications for the design of novel therapeutic
approaches. J Mol Med 1999, 77:412-418.
51. Kapurniotu A, Schmauder A, Tenidis K: Structure-based design
43. Ghanta J, Shen CL, Kiessling LL, Murphy RM: A strategy for
and study of non-amyloidogenic, double N-methylated IAPP
designing inhibitors of b-amyloid toxicity. J Biol Chem 1996,
amyloid core sequences as inhibitors of IAPP amyloid
formation and cytotoxicity. J Mol Biol 2002, 315:339-350.
44. Pallitto MM, Ghanta J, Heinzelman P, Kiessling LL, Murphy RM:
52. Rijkers DTS, Hoppener JWM, Posthuma G, Lips CJM, Liskamp
Recognition sequence design for peptidyl modulators of
RMJ: Inhibition of amyloid fibril formation of human amylin by
b-amyloid aggregation and toxicity. Biochemistry 1999,
N-alkylated amino acid and a-hydroxy acid residue containing
peptides. Chemistry 2002, 8:4285-4291.
Current Opinion in Structural Biology 2003, 13:1–7
Das Noonan-Syndrom Gregor Schlüter1, Malte Rossius1, Armin Wessel2, Barbara Zoll1 Zusammenfassung tyrosin-Phosphorylase, die eine zentrale Regu- that are set low and rotated posteriorly, steno- latorfunktion in fast allen Signaltransduktions- sis of the pulmonal valve and short stature. Das Noonan-Syndrom ist ein Dysmorphie-Syn- wegen von Wachstumsfaktoren ausübt. Diese
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