protein misfolding diseases (current and emerging principles and therapies) || chemistry and biology...

PART V

APPROACHES FOR NEW ANDEMERGING THERAPIES

41CHEMISTRY AND BIOLOGY OFAMYLOID INHIBITION

MARK A. FINDEIS

Satori Pharmaceuticals Incorporated, Cambridge, Massachusetts

INTRODUCTION

Amyloid and amyloidlike diseases are characterized by the pathologicalaccumulation of aggregated, insoluble, and fibrillar protein deposits associatedwith cellular and organ dysfunction. These deposits are classically distinguishedby their tinctorial properties, including the birefringent red–green stainingproduced with Congo Red and the fluorescent dye shifts observed withthioflavins [1]. The most extensively studied of these diseases is Alzheimerdisease (AD), which is associated with the aggregation and deposition ofamyloid beta-peptide (A-beta, Ab). Early efforts to identify disease-modifyingtherapeutic approaches to treat these diseases focused on the idealized goal ofpreventing the formation of the pathological deposits. Progress in under-standing the process of amyloidogenic peptide formation, followed by sub-sequent aggregation and deposition, has resulted in a refined focus on earlierevents in aggregation in which still soluble forms of aggregated amyloidogenicpeptide and protein are mediating cellular toxicity [2,3]. These observationsdemonstrating the pathological significance of soluble amyloid oligomersemphasize their importance when considering how to screen for and character-ize potential inhibitors of amyloidosis.

Therapeutic approaches to mechanism-based disease-modifying interventionin amyloid diseases include at least four broad approaches: block the produc-tion of the amyloidogenic peptide or protein, block its ‘‘misfolding’’ or

Protein Misfolding Diseases: Current and Emerging Principles and Therapies,Edited by Marina Ramirez-Alvarado, Jeffery W. Kelly, and Christopher M. DobsonCopyright r 2010 John Wiley & Sons, Inc.

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transformation from a nonpathogenic monomer or low-oligomer to toxicoligomers and polymers, block the toxic effects of amyloid, or modulate anauxiliary cellular pathway in a manner that affects beneficially one or moreof the foregoing approaches. Depending on the target disease and the level ofknowledge about the production, processing, and clearance of the targetpeptide or protein, each of the approaches above will have varying levels oftractability. In the case of AD and Ab, sufficient research has been accom-plished to demonstrate all of these approaches at least at the cellular level, andthe same is being done for other diseases.

Because the amyloid diseases are diseases in which a normal and known, orpresumably, beneficial (if not fully understood) peptide in the monomericor low-oligomeric state is transformed through conformational change andpolymerization into toxic high oligomers and pathological deposits, they are atoxic gain-of-function process. The most specific intervention in the amyloidcascade would thus be to prevent the conversion of normal nonpathologicalforms of peptide to those that are toxic. In this chapter we discuss theseapproaches, with a particular emphasis on Ab, where at present there is thelargest and most varied body of research in these methods.

MACROMOLECULAR INHIBITORS OF AMYLOID FORMATION

A large variety of macromolecules have been described that modulate theaggregation of amyloidogenic proteins. The complex biological milieu in vivoprovides many different macromolecules that have been demonstrated to interactwith one or more amyloidogenic proteins. Many proteins are observed associatedwith amyloid deposits. Whether these observations reflect an interaction thathappens before aggregation and deposition, and whether the interaction isinhibitory or promoting with respect to aggregation, is not always clear. Forproteins associated with deposits, even if a specific interaction, we do not typicallyhave firm data on whether the additional protein has any influence on pathology.With this general caveat inmind, there are three types ofmacromolecules that havereceived considerable attention as modulators of amyloid formation: antibodiesagainst Ab, glycoproteins, and apolipoprotein E (ApoE). In each case themolecular-level details of how these macromolecules interact with their targetare notwell defined. But, in turn, newopportunities have emerged that have addedto efforts to discover small-molecule antagonists of amyloidosis.

ANTIBODIES AND IMMUNOTHERAPY

The most advanced disease-modifying approach to treating a major amyloiddisease is that of using immunotherapy for AD. This approach has progressedto clinical trials in humans based on compelling results in animal models. Earlyresearch demonstrated that antibodies against Ab could inhibit its aggregationin vitro [4,5]. Subsequently, active vaccination of transgenic animals with Ab in

906 CHEMISTRY AND BIOLOGY OF AMYLOID INHIBITION

various forms and passive vaccination (administration of previously madeantibody) were shown to provide apparent benefits in animals with respect toamyloid deposition and pathology [6] as well as cognitive performance [7,8].Progress in the clinic has been slowed due to side effects observed in the firsttrial, but many variations of how to design vaccines and engineer antibodieshave been the subject of ongoing research, and revised immunotherapies willcontinue to enter development.

From a mechanistic point of view, the antagonism of Ab amyloidosis byantibodies thoroughly validates the concept that misfolding of amyloidogenicpeptides can be inhibited by the binding of a structural element (e.g., therelatively large antibody) that sterically interferes with conformational changesand/or subsequent polymerization processes. In addition, binding of antibodiesis expected to promote clearance of its target peptide through preservation ofits solubility and prevention from deposition.

APOLIPOPROTEIN E

The first significant risk factor identified for acquisition of sporadic late-onsetAD, in addition to age, was related to allelic variation of ApoE. Individualshomozygous for ApoE4 were found to be more likely to acquire AD than thosewith genes for ApoE2 and ApoE3 [9]. Upon observing that ApoE genetics wererelated to risk of AD, ApoE was found to interact with Ab [10]. Further, ApoEwas observed to be an inhibitor of Ab aggregation, with ApoE4 being lesseffective than ApoE3 [11]. From this point of view, ApoE4 may not be so mucha positive contributor to risk for acquiring AD as a less effective protectantfrom AD. Whether direct interactions of ApoE with Ab, or its role in lipidmetabolism, represent phenomena that can be exploited for treatment of ADremains to be determined. ApoE and a number of other proteins are alsoassociated with interactions with Ab and APP processing that have beenstudied and may present additional opportunities for drug discovery [12].

SMALL-MOLECULE INHIBITORS OF AMYLOIDOSIS

A variety of relatively low molecular weight inhibitors of amyloid aggregationhave been described. For the purposes of the present discussion, thesecompounds can be described as derived from a range of molecular types,that including peptides, carbohydrates, and glycoproteins (and related com-pounds), and organic compounds.

Peptides

Early experiments in which site-specific changes in the sequence of Ab weremade using chemical synthesis identified sites in the Ab sequence that appeared

SMALL-MOLECULE INHIBITORS OF AMYLOIDOSIS 907

to be quite important in promoting or allowing folding of the peptide into aform that would allow amyloidosis [13–15]. In particular, the Phe–Phe dipep-tide at position 19–20 in Ab was identified as important. Long Ab peptides inwhich these two residues were changed to smaller nonaromatic residues werefound to be less competent to form amyloid fibrils and also to act as inhibitorsof the fibrillization of wild-type Ab. The suggestion was made that suchnonamyloidogenic long peptides might even have potential therapeutic use[14]. Subsequent experiments by Tjernberg et al., [16] used an iterative processof spot synthesis of short peptides and binding to Ab-identified short peptidesbased on Ab(16–21), KLVFF, with high affinity for Ab and the ability to act asinhibitors. Soto developed the concept of ‘‘beta-sheet breaker’’ peptides basedon the inclusion of a prolyl residue which was reported to improve inhibitoryactivity ([17]; and see Chapter 43), although this series of compounds has beencited as less active than related nonprolyl peptides in some assays [18–20].Somewhat related approaches were undertaken by others using a, a-dialkylamino acids [21] and N-methyl peptides to achieve similar effects [18,22]. In thesame time frame, the Praecis Pharmaceuticals group had already undertakensystematic studies of these and other approaches to the adaptation of smallpeptides as inhibitors of amyloidosis and identified alternative preferredapproaches. Initially their main approaches were based on organic-modifiedpeptides of various lengths [23–26], and with further optimization, theidentification of sequence-modified ‘‘enhanced’’ Ab peptide derivatives withpotent antifibrillization activity [19,20,27]. An extensive series of inverso (all-D)and retro-inverso (all-D reverse sequence) peptides included a compoundnumbered PPI-1019, N-methyl-D-Leu-D-Val-D-Phe-D-Phe-D-Leu-amide, whichprogressed through phase 1 clinical trials [27]. While the intention to beginphase II trials in AD patients was announced by Praecis, this effort was put onhold, apparently due to business-restructuring issues.

Glycoprotein Mimetics

Identification of glycoproteins and glycosaminoglycans (GAGs) in AD plaquesin association with Ab prompted further studies that found that these proteinsand polysaccharides could bind to Ab with high affinity [28]. These observa-tions led to the development GAG-mimetics which inhibit amyloidosis [29,30].The most advanced examples of this approach are experimental drugs beingdeveloped by Neurochem, including tramiprosate (3-aminopropanesulfonicacid) for AD and eprodisate (propanedisulfonic acid) for amyloid A amyloi-dosis. Both compounds have been the subject of phase III clinical trials and arebeing considered for marketing approval. Less than robust clinical data mayrequire further study to gain approval but do suggest that aggregationinhibitors have clinical promise.

In other work based on the study of phosphatidylinositols, neutral inositolswere found to inhibit aggregation [31]. Quite notably, while peptide inhibitorsare reported to maintain Ab in a monomeric state, inositols were found to


stabilize an oligomeric form of Ab which was nontoxic to cells. Similarly to theGAG mimetics, these sorts of inhibitors does not appear to be as potent asthe high-affinity peptide inhibitors, but appear to be very safe, very soluble, andtherefore acceptable in profile for clinical development [32,33].

A related polyol, the disaccharide trehalose ((1-a-D-glucopyranosyl-1-b-D-glucopyranoside) is also reported to inhibit Ab aggregation [34]. Careful studyof this inhibitor revealed that it was less potent for Ab42 relative to the lessamyloidogenic Ab40. Importantly, inhibition was retained for mixtures ofAb40 and Ab42.

Small Organics

Early screening efforts to identify inhibitors of Ab aggregation from libraries oforganic compounds appear to have been undertaken by a number of pharma-ceutical companies as well as academic labs, starting in the early 1990s if notearlier. A general result of these efforts is that a variety of compounds(reviewed elsewhere, and beyond the scope of this chapter) with activity weredescribed, but none proved robust enough in potency or drugability to reachclinical development. A particular challenge in early screens was the rather highconcentration of Ab used in assays and a resulting difficulty in discerningwhether apparently potent compounds were merely ‘‘good’’ or ‘‘excellent’’ andsupportive of further work. Persistence on the part of experienced investigatorsand those new to the field have provided more recent progress, however, oftenfrom interesting and divergent starting points. Among the compounds thathave been reported with direct or indirect inhibitory activities are curcumin [35]and the structurally related ferulic acid [36], methylene blue [37], aryl aminoacid derivatives [38], naphthalene sulfonates [39], and metal chelators [40]. Inaddition to histological dyes such as Congo Red and the thioflavins T and S, ageneral structural theme among these compounds is some degree of aromaticityand hydroxylation or other heteroatomic elaboration [41] presumably tosupport a mixture of hydrophobic interactions and hydrogen bonding, whosespecificity is not yet elucidated.

MECHANISMS OF ACTION

Attempts to understand the mechanisms of action of any of these inhibitors arelimited by the level of understanding amyloid structure, particularly in thecontext of protein–inhibitor complexes. Sophisticated structural studies of Abunder varying solvent conditions or polymer state reveal very differentstructures (Fig.1) [42–45]. The only clear detail in this regard is that fromstudies of transthyretin in which a stable native tetramer provides a cavity inwhich stabilizers of the native state can be studied by protein structuralmethods, including crystallography (see Chapter 45). For those amyloidoseswhere a stable native state is not available for study, one is left to infer about

MECHANISMS OF ACTION 909

the mechanism based on structure–activity relationships (SARs) of differentrelated compounds and differences in the effects of inhibitors at different stagesof the amyloid cascade.

In the case of the peptide-based inhibitors of Ab aggregation, there is adecent level of experimental data to suggest that a particular site of binding isthe hydrophobic core of Ab at positions 17 to 21, Leu–Val–Phe–Phe–Ala or(LVFFA). The affinities between synthetic peptides of varying sequence and Ab[16] and the SAR of ‘‘enhanced’’ inverso and retro-inverso peptidic inhibitorsof Ab aggregation ([27] and references therein) support a model in whichpeptidic inhibitors bind to an amyloidogenic target in which the target hasalready (or, concomitantly) adopted a beta-structured state but is not yet in atoxic oligomeric or fibrillar form. Studies of the solubility and conformationalproperties of mixtures of D-and L-polyamino acids which show low solubility[46] and transition to beta-sheet-rich structure [47] are consistent with theseobservations. More recent studies suggest that the thermodynamic drivingforce for the stability of ‘‘diastereomeric’’ beta-structured peptide complexes isa greater reduction of hydration and a corresponding savings in entropy [48].

Evidence for a strong interaction of inhibitors with beta structure is seen inthe use of a fibril-binding assay which can document subnanomolar dissocia-tion constants of potent peptidic inhibitors [19,20]. Given the efficacy of

A

B

C

?

FIG. 1 Dynamic structure of amyloid beta peptide in different states of environment

and self-assembly (PDB file number, reference): (A) monomer as collapsed coil in water

(1HZ3, [42]); (B) highly helical monomer in 80% hexafluoro isopropano l–20%water

(1IYT, [43]); (C) fibrillar Ab (2BEG, [44]; see also [45]). Not shown is a representation of

toxic soluble oligomeric amyloid.


such compounds to block fibrillogenesis and maintain Ab in a monomericor low-oligomeric state [26], it suggests that even in a prefibrillar nontoxic state,a completely or substantially beta-structured binding site for the inhibitormay exist.

Attention to both biophysical studies and cellular toxicity are importantmeasures to be used together to evaluate the properties of potential inhibitors.As noted above, compounds such as the inositols can stabilize a non toxic butoligomeric form of Ab. By some screening approaches, the presence ofoligomer would disqualify a compound as not useful. By also examiningcellular toxicity, an uncommon pairing of properties was noted. By contrast,naphthalene sulfonates such as bis-ANS also stabilize low oligomers of Ab,but these oligomers are toxic [39]. Other compounds are able to inhibitfibrillization but not oligomerization [49]. Although such compounds mightslow accumulation of amyloid deposits, they might not have any impact onacute toxicity associated with soluble oligomers and in fact might exacerbateit. In the case of trehalose, its potency-inhibiting Ab40 aggregation contrastswith it much reduced potency against Ab42. Whether the lesser potencyagainst Ab42 represents a liability that would keep such a compound fromworking therapeutically remains to be determined. In the case of AD and Ab,a question such as this becomes quite important. When mixed with Ab42,Ab40 inhibits the aggregation of Ab42 [50]. If an inhibitor were somehow to beselective in a manner that reduced the ratio of Ab40 to Ab42 (e.g., by amechanism involving binding and facilitated clearance), such an effect mightactually be promoting of disease [12].

SUMMARY

A variety of inhibitors of aggregation and fibrillization of amyloidogenicproteins have been described. Limited molecular detail is available to fullydescribe the mechanism of action of these compounds, except in special cases.Fully profiling the characteristics of compounds through SAR studies andmultiple forms of biophysical, cellular, and in vivo assays is essential to fullycorrelate interactions of a compound with its target and any associatedpotential therapeutic benefit. Past and current progress is now bringingamyloid inhibitors into clinical trials and the ability of discovery techniquesto provide drug candidates that will benefit patients is being addressed.

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