[Molecular Medicine and Medicinal Chemistry] Alzheimer's Disease: Insights into Low Molecular Weight...

November 26, 2012 10:1 9in x 6in Alzheimer’s Disease: Insights Into Low Molecular … b1377-chA6

6Inhibitor Design Against

Cytotoxic β-Amyloid Species

Andrew J. Doig∗

6.1 Introduction

6.1.1 Alzheimer’s disease and β-amyloid

Alzheimer’s disease (AD) is characterized pathologically by abnormallyhigh levels of brain lesions (senile plaques) and neurofibrillary tangles indead and dying neurons, and by elevated numbers of amyloid deposits inthe walls of cerebral blood vessels. The major component of senile plaquesis a small peptide of 39–43 amino acids called β-amyloid (Aβ), whichreadily self-assembles into amyloid fibrils. Longer variants of Aβ are moreprone to form amyloid. Aβ is produced through endoproteolysis of theamyloid precursor protein (APP). APP is first cleaved by β-secretase togive the membrane-bound C99 peptide and then by γ-secretase to give Aβ.Compelling evidence indicates that factors that increase the productionof Aβ, particularly its more amyloidogenic variants, or that facilitatedeposition or inhibit elimination of amyloid deposits cause AD or are riskfactors for the disease (Selkoe, 1999).

∗Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street,Manchester M1 7DN, UK. Phone: +44 161 3064224; Fax: +44 161 3068918; Email:[email protected].

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188 A. J. Doig

6.1.2 β-Amyloid oligomers

Although Aβ aggregation clearly leads to Aβ toxicity, the structures ofaggregated Aβ were not initially studied closely, leading to the assumptionthat it was the readily visualized large fibrils that were toxic. Controversyraged over whether the fibrils are an epiphenomenon linked to disease orwhether fibril formation causes disease (Robinson and Bishop, 2002). Forexample, although many mutations in the Aβ precursor protein gene arelinked to premature onset of AD, the amount of amyloid deposited in thebrain does not correlate with severity. A resolution of this apparent paradoxfrom in vitro and in vivo evidence is that soluble, oligomeric forms of Aβ

have potent neurotoxic activity and are the primary cause of neuronal injuryand cell death occurring in AD (Lambert et al., 1998; Klein et al., 2001; Lesnéet al., 2006; Haass and Selkoe, 2007; Walsh and Selkoe, 2007). The primarytarget of an Aβ-based therapy should therefore be Aβ oligomers, ratherthan other less toxic or non-toxic species.

Evidence for the involvement of soluble, non-fibrillar Aβ in AD hasbeen obtained from synthetic Aβ peptides, cell culture systems that over-express APP, APP transgenic mice, and human cerebrospinal fluid andpostmortem brain (reviewed by Walsh and Selkoe, 2007). Sodium dodecylsulfate-stable dimers and trimers of Aβ were found in human cerebrospinalfluid (Vigo-Pelfrey et al., 1993) and postmortem brains (McLean et al.,1999). Lesné et al. (2006) used the Tg2576 transgenic mouse model tosearch for Aβ aggregates, the presence of which correlates with cognitivedecline, notably in the Morris water maze test, where performance in thesemice is notably different to wild-type from six months. They found thatnonamers and dodecamers first appear at this time and their levels correlatewith memory deficits. Injection of dodecamer into the ventricle of normalpretrained wild-type rats caused a dramatic fall-off in spatial memoryperformance, leading them to conclude that it is the dodecamer (Aβ56∗)that is the primary toxic species of Aβ (Lesné et al., 2006). 7PA2 Chinesehamster ovarian cells express mutant (V717F) human APP, and henceproduce and secrete low nanomolar amounts of Aβ (Podlisny et al., 1995).These have proved to be a valuable source of sodium dodecyl sulfate-stablelow-n Aβ oligomers that migrate in denaturing gels as dimers, trimers,and occasionally tetramers (Walsh et al., 2002). 7PA2 conditioned medium

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Inhibitor Design Against Cytotoxic β-Amyloid Species 189

inhibits hippocampal long-term potentiation (Walsh et al., 2005) andadversely affects performance in the alternating lever cyclic ratio test in rats(Cleary et al., 2005). The number of neuronal dendritic spines was dramati-cally decreased when neurons were grown in the presence of sub-nanomolarconcentrations of cell-derived Aβ oligomers (Shankar et al., 2007).

In this review, I briefly cover different strategies to treat AD, concen-trating on molecules able to inhibit Aβ aggregation and, ideally, affect thestructures or populations of Aβ oligomers. Such molecules can be foundin various ways, such as by screening libraries of compounds. Alternatively,knowledge of Aβ sequence and structure can be used to rationally designinhibitors (most often peptides).

6.2 Alternative Strategies to Treat Alzheimer’s Disease

A range of strategies are possible to prevent key steps within the amyloidcascade that leads to cell death, initiated by the key event of Aβ aggregationand oligomer formation. The main current approaches are briefly describedhere. As Aβ is produced by the cleavage of APP by β- and γ-secretase,inhibitors of either of these enzymes should prevent production ofAβ. Although numerous effective inhibitors of these targets have beendiscovered, there is concern that their inhibition would cause undesirableside-effects. For example, the deletion of β-secretase (β-site of APP-cleaving enzyme (BACE1)) in mice resulted in an increased death rate,reduced size, and alterations in the steady-state inactivation of voltage-gated sodium channels (Dominguez et al., 2005). BACE1 is also involvedwith the control of peripheral nerve myelination (Willem et al., 2006).Presenilin, the catalytic member of the γ-secretase proteolytic complex,has numerous substrates and roles in addition to cleaving APP, notably inreleasing the transcriptionally active domain of the receptor Notch (Parksand Curtis, 2007). A recent report, however, provides encouragementfor the γ-secretase-based strategy by identifying a γ-secretase activatingprotein that increases Aβ production without affecting Notch (He et al.,2010). Hence, inhibition of this protein may decrease Aβ levels without theunwanted side-effects of other γ-secretase inhibitors.

Immunization with Aβ showed exciting results in preventing the onsetof Aβ-related pathology in a transgenic mouse (Schenk et al., 1999),

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190 A. J. Doig

although a subsequent clinical trial had to be halted after a small number ofpatients developed meningoencephalitis (Nicoll et al., 2003). Nevertheless,vaccination remains a promising approach, perhaps using fragments ofAβ or other modifications. Activated microglia, along with a range ofinflammatory mediators,have been identified in association with the lesionsof AD, implying that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs could protect against the disease, a hypothesis that issupported by epidemiological investigations (McGeer and McGeer, 2007).Although the major toxic species in AD is probably Aβ oligomers, and hencethese would be the principal target of an AD drug, it remains unclear why Aβ

oligomers should be toxic. Plausible mechanisms of toxicity include linksto oxidative stress, metal binding, free radical formation (Chauhan andChauhan, 2006), or ion channel formation (Quist et al., 2005), so it maybe possible to interfere with these processes, using reducing agents, metalchelators (Bush, 2002), or ion channel inhibitors. Using stem cells to replacelost neurons is a possibility for the future, although this approach wouldnot remove the toxic material. Current well-established AD drugs, suchas Donepezil (Aricept™), ENA-713 (Exelon™), Galantamine (Reminyl™),Memantine (Namenda™), and Tacrine (Cognex™) are acetylcholinesteraseinhibitors or N-methyl-D-aspartate receptor antagonists. They can onlyalleviate symptoms for a limited time.

Another strategy could be to activate α-secretase, which cleaves APPin the middle of the Aβ sequence. Several intracellular signalling pathwaysactivate α-secretase, such as muscarinic acetylcholine receptor stimulationand mitogen-activated protein (MAP) kinase activation. A disintegrin andmetalloproteinase (ADAM) enzymes are inactivated by tissue inhibitorsof metalloproteinases, and decreased levels or activity of specific tissueinhibitors of metalloproteinases may facilitate α-secretase cleavage (Postina,2008). Side-effects due to multiple roles of these enzymes and pathways areproblematic.

Numerous enzymes, including neprilysin, insulin-degrading enzyme,endothelin-converting enzyme, angiotensin-converting enzyme, matrixmetalloprotease-9, and plasmin are known to be involved in Aβ degradation(Howell et al., 1995; Qiu et al., 1998). Hence, strategies that enhance theactivity or protein levels of these proteases might be effective for thetreatment of AD. For example, the G-protein coupled receptor GPCR

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receptor analogue, somatostatin, significantly increased neprilysin activityand hence treatment of primary neurons with somatostatin leads to areduction of Aβ levels (Saito et al., 2005).

In general, one would want to interfere with the first step of a pathwaythat leads to disease. Treatments designed to target steps that followprotein/peptide aggregation are less likely to be effective because they wouldnot prevent the formation of toxic soluble oligomers, which could continueto kill cells. An attractive therapeutic strategy in principle is therefore toinhibit peptide aggregation and oligomer formation, because this appearsto be the first step in the pathogenic process of amyloidosis that is notassociated with some natural biological function. Hence, the main focus ofthis chapter is on molecules designed to bind to cytotoxic Aβ species andinterfere with Aβ aggregation.

6.3 Inhibitors of β-Amyloid Toxicity

6.3.1 Peptides

Many reported inhibitors of Aβ aggregation and toxicity are peptides. Stud-ies in vitro on fragments of amyloidogenic proteins and synthetic peptideshave established that the tendency for a protein to form amyloid is oftenlimited to a short sequence of the full protein, known as a “self-recognitionelement” (SRE) (Madine et al., 2008; Tzotzos and Doig, 2010). SREs formthe core of amyloid fibrils. These amyloidogenic sequences constitute “hotspots” for aggregation of the native protein into amyloid fibrils and areoften the sites of mutations leading to early-onset amyloidosis. In the caseof tau paired helical filaments, which accumulate in the neurofibrillarytangles characteristic of AD and other neurodegenerative diseases, it hasbeen shown that only three residues, VYK, are sufficient for fibril formation(Goux et al., 2004). Short sequences forming the core domains of variousother amyloid fibrils have been identified, amongst which are KLVFFAE forAβ (Balbach et al., 2000), NFGSVQ for medin (Reches and Gazit, 2004),DFNKF for calcitonin (Reches et al., 2002), FGAIL and NFGAIL for isletamyloid polypeptide (Tenidis et al., 2000),VEALYL and LYQLEN for insulin(Sawaya et al., 2007), and VAQKTV for α-synuclein (Madine et al., 2008).It is often possible to delete residues freely on either side of an SRE whileretaining the ability to form amyloid. These SREs can be used as the basis

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192 A. J. Doig

Figure 6.1. Aβ self-recognition element Ac-KLVFF-NH2.

for the rational design of inhibitors of Aβ aggregation and toxicity as theyare already known to bind to the full-length target peptide.

Tjernberg et al. (1996) showed that Aβ(16-20), sequence KLVFF(Fig. 6.1), was able to bind full-length Aβ and prevent its assemblyinto fibrils. Using molecular graphics simulations they hypothesized thatit bound stereospecifically and in an antiparallel conformation to Aβ

(Tjernberg et al., 1997). Despite being shown to form fibrils in isolation,Aβ(16-20) was proposed as being a key region from which a lead compoundcould be created against amyloid, and indeed most groups have made useof this sequence as a starting point. Aβ(16-20) composed entirely of D-amino acids was as effective as its all-L-analogue with the additional benefitof being protease resistant (Tjernberg et al., 1996). Longer peptides thatretain the 16-20 region, namely 15-22, 16-23, and 17-24, can also inhibitAβ aggregation (Matsunaga et al., 2004). RIIGL, based on Aβ(31-34), whichhas the sequence IIGL, can also inhibit fibril formation by Aβ (Fülöpet al., 2004), so may also act as a starting point for modified peptideaggregation inhibitors. Similarly, GVVIA-NH2 and RVVIA-NH2, whichare based on Aβ(38-42), can inhibit Aβ aggregation and toxicity (Hetényiet al., 2002). Schwarzman et al. (2005) screened a combinatorial peptidelibrary for Aβ aggregation inhibition and found several novel peptidesequences that may be similarly useful. Their hits contained consensussequences ++Hy+(Hy/+), ++XX+, (D/E)LVXHy, or +LVLF, where + isa positively charged residue, Hy is a hydrophobic residue, and X is variable.

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Key amyloidogenic regions often contain positively charged Lys or Arg, aswell as hydrophobic residues (Tzotzos and Doig, 2010), which is consistentwith these findings. If these amyloidogenic regions of Aβ could be modifiedto retain binding, but then prevent the association of further Aβ molecules,we would have an inhibitor of Aβ aggregation. A number of groups havefollowed this strategy, by modifying Aβ in various ways, as described below.

Soto et al. (1996) designed inhibitors aimed at the core region of Aβ,in this case residues 17-21. Their strategy is based upon substituting keyresidues for prolines in a bid to reduce the β-propensity. It is difficult tounderstand how preventing the adoption of the β conformation presentin aggregated Aβ could still allow binding. Nevertheless, a five-residuepeptide (LPFFD) with the ability to prevent fibril formation was found.All D-analogues were again found to be as effective, but with increasedprotease resistance. These so-called“β-sheet breakers”were then shown notonly to be stable in vivo, but to be small and hydrophobic enough to haveblood–brain barrier permeability (Soto et al., 1998; Poduslo et al., 1999).

Based initially around the 15-25 region of Aβ, Murphy and co-workers (Ghanta et al., 1996; Pallitto et al., 1999; Lowe et al., 2001)designed a peptide with a “recognition element” homologous to the Aβ

peptide, and a “disrupting element”, tagged to the C-terminus, designed tointerfere with the Aβ aggregation. For example, KLVFFKKKK acceleratedAβ aggregation kinetics, altered fibril morphology, and reduced toxicity.The anionic disrupting KLVFFEEEE had similar effects, whereas the neutraldisrupting KLVFFSSSS was ineffective, suggesting that the hydrophilicnature of the disrupting element is critical. Aβ aggregation need notbe blocked to prevent toxicity, as the compounds work by acceleratingaggregation to remove toxic soluble oligomers (Kim and Murphy, 2004).Moss et al. (2003) have disputed some of the results on KLVFFKKKKKK,however, as they found no reduction in Aβ toxicity, as measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), eventhough the molecule did enhance protofibril association. Cairo et al. (2002)used binding to Aβ(10-35) monitored by surface plasmon resonance tomeasure the affinities of peptides to bind to Aβ. The peptides studied wererelated to KLVFF and some again had up to six charged residues at the C-terminus. No pentapeptides were found to be more effective than KLVFF,whereas the addition of up to six positively charged residues was found

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194 A. J. Doig

to favour binding. Converting some of the C-terminal Lys side-chains bymethylation to betaine [(CH3)3N+CH2COO−] increased activity,probablyby specific binding by KLVFF, increasing surface tension, and inducing Aβ

aggregation into a less toxic form (Kim et al., 2003). Further modificationsto the K6 sequence within the KLVFFKKKKKK inhibitor included branchedrather than linear lysine, L-lysine replaced by D-lysine, lysine replacedby diaminopropionic acid, and lysine replaced by arginine. A similarstrategy was employed by Burkoth et al. (1998) who attached a disruptingpolyethylene glycol block to the amyloidogenic fragment Aβ(10-35), givingan inhibitor of Aβ(10-35) fibrillogenesis.

Findeis et al. (1999) analysed many truncated variants of Aβ with a vari-ety of different N-terminal modifications, to establish a small, yet effective,inhibitor of Aβ polymerization. The strategy here is to retain a peptide thatcan bind to Aβ, but with a bulky group, such as a steroid, at its terminusto hinder further Aβ association. The all-D-amino acid peptide cholyl-LVFFA-OH was the most effective inhibitor of Aβ polymerization (Findeiset al., 2001), able to delay the onset of polymerization and the formation ofneurotoxic Aβ species by binding to Aβ within a fibrillar structure.

Several groups are studying the incorporation of N-methyl aminoacids into peptides as inhibitors of amyloidosis. These peptides againcorrespond to a region that is key to the amyloid protein. One side presentsa hydrogen-bonding “complementary” face to the protein, with the otherhaving N-methyl groups in place of backbone NH groups, thus presentinga “blocking” face. The N-methyl group also induces β-structure at theN-methylated site. Substituting a residue with an N-methyl group is similarto substituting with a Pro (above), as both will prevent backbone hydrogenbond donation. An N-methyl group is constrained to a β conformation,however, unlike Pro. Hughes et al. (2000) showed that N-methyl derivativesof Aβ(25-35), an aggregation-prone and toxic fragment of Aβ, were ableto prevent aggregation and inhibit toxicity in PC-12 cells. The location ofthe N-methyl group was critical, with some of the most effective inhibitorsaltering fibril morphology, rather than preventing Aβ(25-35) aggregation,as anticipated. Meredith and co-workers (Gordon et al., 2001; Gordon et al.,2002) investigated N-methylated peptides of a region corresponding to16-22 and later 16-20 of the amyloid “core domain” region. They preventedAβ fibrils from forming and broke down preformed fibrils. It is essential

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that multiple N-methylations are on the same side of the peptide when ina β conformation, i.e. all at odd or all at even positions, so that the peptideretains an unblocked binding face. Although most of this work started withKLVFF, Cruz et al. (2004) used N-methylated inhibitors based on Aβ(36-40)(VGGVV). Kokkoni et al. (2006) optimized the structure of an inhibitorof Aβ aggregation and toxicity by starting with KLVFF and varying theside-chain identity, chirality,N-terminal acetylation,C-terminal amidation,and location of N-methyl groups. After four rounds of optimization,the most active compound was found to be D-[(chGly)-(Tyr)-(chGly)-(chGly)-(mLeu)]-NH2 (SEN304; Fig. 6.2), where every group had changedfrom the starting sequence, though retaining the pentapeptide framework.Inhibitors that had the N-methyl group replaced with an NH were highlyinsoluble and often toxic.

PPI-1019 D-(H-[(mL)VFFL]-NH2) is another effective N-methylatedpeptide inhibitor of Aβ aggregation and toxicity (Findeis, 2002). It isfundamentally different from other N-methylated peptides, however, asthe methylation of the unacetylated N-terminus means that an amineis methylated, rather than an amide, which would be the case at otherpositions. A singly methylated amine still has two hydrogen bond donors,so its mode of action may well be different to peptides that have methylatedamides, where hydrogen bond donation is eliminated. N-methylation ofthe N-terminal amine in Aβ(25-35) has no effect, for example, whereasN-methylation at other sites prevents the peptide being amyloidogenic(Hughes et al., 2000).

Figure 6.2. Peptidomimetic Aβ aggregation inhibitor SEN304.

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196 A. J. Doig

The peptide OR2 (RGKLVFFGR-NH2) is again based on KLVFF, butwith Arg-Gly sequences added to each terminus to improve solubility.This inhibited Aβ oligomer formation and reduced toxicity of Aβ inneuroblastoma SH-SY5Y cells (Austen et al., 2008). As a nine-residuepeptide is likely to be readily hydrolysed in vivo, the OR2 peptide wassubsequently converted to a retro-inverso peptide (RI-OR2), where all ofthe natural L-amino acids are replaced with the D-enantiomer, and thepeptide bonds are reversed (Taylor et al., 2010). This retains the side-chaingeometry of the parent peptide, but gains the beneficial effects of usingD-amino acids. RI-OR2 blocked the formation of Aβ oligomers and fibrils,bound to immobilized Aβ(1-42) monomers and fibrils, and reversed thetoxicity of Aβ(1-42) toward SH-SY5Y cells.

The tandem peptide construct Aβ40-1-(Gly)8-Aβ1-40 links two copiesof Aβ and inhibits Aβ fibrillization at low inhibitor : Aβ ratios (Mustafi et al.,2010), although it is doubtful whether such a large unmodified peptidewould be effective in vivo.

The dipeptide NH2-D-Trp-Aib-OH combines a Trp,as aromatic groupsare known to interact with Aβ, α-aminoisobutyric acid, which cannot formβ structure, and D-amino acids. It stabilizes non-toxic small oligomers andinhibits their growth into larger toxic structures. Most encouragingly, itreduces Aβ toxicity in cells, improves cognitive performance in mousemodels for AD, crosses the blood–brain barrier, and has acceptablepharmacokinetic properties (Frydman-Marom et al., 2009).

The peptide backbone can also be modified by replacing an amidegroup with an ester. This will remove the ability to hydrogen bond,but without adding any steric bulk or strongly affecting the backboneconformation, unlike N-substitution. KLVFF with an ester substitution wasalso able to inhibit the aggregation of Aβ and to disassemble preformed Aβ

fibrils (Gordon and Meredith, 2003). However, one would expect an estergroup to be rapidly hydrolysed in vivo.

6.3.2 Small molecules

Numerous organic compounds have been found to inhibit orreduce the aggregation and toxicity of Aβ in vitro. These includenicotine (Salomon et al., 1996; Moore et al., 2004), β-cyclodextrin(Camilleri et al., 1994), hemin and related porphyrins (Howlett

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et al., 1997), anthracycline 4′-iodo-4′-deoxydoxorubicin (Merlini et al.,1995), hexadecyl-N-methylpiperidinium bromide (Wood et al., 1996),rifampicin (Tomiyama et al., 1996), (–)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronapthalene (Parker et al., 2002), typeIV collagen, a molecule that localizes in senile plaques of patients with AD(Kiuchi et al., 2002), melatonin (Pappola et al., 1998), danuomycin (Howlettet al., 1999), glycosaminoglycans (McLaurin et al., 1999), fullerene (Kim andLee, 2003), 3-amino-1-propanesulfonic acid (Alzhemed or Tramiposate)(Aisen et al., 2006), apomorphine derivatives (Lashuel et al., 2002), 3-indole propionic acid (Bendheim et al., 2002), nordihydroguaiaretic acid,tannic acid, and quercetin (Matsuzaki et al., 2007), phenylazo benzenesul-fonamides (Lin et al., 2004), amphiphilic surfactants (Wang et al., 2005),curcumin (Yang et al., 2005), oligomeric acylated aminopyrazoles (Rzepeckiet al., 2004), cyclohexanehexol (inositol) stereoisomers (McLaurin et al.,2000; McLaurin et al., 2006), methylene blue (Necula et al., 2007),polyphenol (–)-epigallocatechin (Ehrnhoefer et al., 2008), and polyphenols(Porat et al., 2006). Salvianolic acid B directly inhibits PC12 cellular toxicityof aged Aβ (Tang and Zhang, 2001). Aβ aggregation can be induced byacetylcholinesterase, which can be inhibited by �9-tetrahydrocannabinol(Eubanks et al., 2006). Bifunctional inhibitors can be created by covalentlylinking an Aβ-binding molecule (Congo red) to a synthetic ligand forthe FK506 binding protein chaperone (Gestwicki et al., 2004). Oligomericacylated aminopyrazoles (e.g. Ampox, Fig. 6.3) with a donor–acceptor–donor hydrogen bond pattern complementary to that of a β-sheet areeffective inhibitors of Aβ aggregation, presumably by binding in the samemanner as a β-sheet peptide (Rzepecki et al., 2004). Caution should beexercised with some of these reports as they are often only based on a smallnumber of biophysical assays. For example, a molecule that interferes withthioflavin T fluorescence, a commonly used reporter for Aβ aggregation,may give artefactual results.

Figure 6.3. Ampox.

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The structural diversity in these molecules is remarkable, suggestingthat they can act in multiple ways and bind to Aβ at many different sites, incontrast to competitive enzyme inhibitors, for example, which bind to theenzyme active site as they resemble the substrate. For example, curcumindecreases Aβ levels by modulating APP processing, rather than interactingdirectly with Aβ oligomers. It increases the retention of immature APP inthe endoplasmic reticulum (ER) and attenuates APP endocytosis from theplasma membrane (Zhang et al., 2010). Few of these small molecule com-pounds are rationally designed using knowledge of the Aβ target sequenceand structure, as can be done more straightforwardly with peptides.

6.4 Conclusions

Although the rational design of compounds binding to Aβ is attractivein principle, this strategy has been mainly applied with peptides, withthe interesting exception of oligomeric acylated aminopyrazoles (Rzepeckiet al., 2004). Peptides generally make poor drugs, however, for severalreasons. Most drugs have properties that follow the Lipinski “rule-of-five”, namely five or fewer hydrogen bond donors, ten or fewer hydrogenbond acceptors, log P ≤ 5, and a molecular weight less than 500 Da.Most of the peptides or peptidomimetics described here do not meet thesecriteria. In addition, peptides are prone to degradation and do not crossmembranes, making them poor drugs. Some of the modifications discussedabove, however, do considerably improve the molecules’ properties, such asN-methylation, using all-D-peptides and unnatural side-chains.

Current results from drugs that have reached late-stage clinical tri-als continue to disappoint (http://www.alzforum.org/new/newssearch.asp?categoryID=22). New drugs for AD, perhaps using designs based on Aβ,as covered above, therefore continue to be an active and potentially veryvaluable research strategy for this massively important disease.

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[Molecular Medicine and Medicinal Chemistry] Alzheimer's Disease: Insights into Low Molecular Weight...

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