Alzheimer’s Disease (AD) is a neurological disorder which affects more
than 37 million people worldwide. However the current Food and Drug
Administration (FDA) approved drugs do not provide for reversal or
prevention of the disease, instead give a modest symptomatic relief
only. But the development of newer agents has gained pace in recent
years with the growing understanding of the molecular pathophysiology of
Alzheimer’s Disease.
Pathogenesis
Two microscopic
features characterize the progression of this disease, namely
extracellular amyloid plaques which consist of amorphous deposits of
ß-amyloid peptide (Ab) and the intraneuronal neurofibrillary tangles
that comprise of the filaments of a hyperphosphorylated form of a
microtubule associated protein (tau).
Current approaches towards therapy of AD
The following approaches are currently employed to retard the process of neurodegeneration in Alzheimer’s Disease:
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Cholinesterase inhibitors- Tacrine, rivastigmine, donepezil and
galantamine administration caused improvement in memory and cognition.
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Decreasing Ab formation by direct binding or reduced transport-
Direct interaction with Aß may reduce aggregation and accumulation thus
limiting synaptic dysfunction and neurotoxicity. Following approaches
are used: a) Tramiprosate- Binds to monomeric Ab and hence reduces its
aggregation and neurotoxicity while also promoting its clearance from
the brain; b) Ab42 vaccines, monoclonal Aß antibodies and polyclonal
antibodies- Antibodies binding to Ab peptide in the blood promote
microglial phagocytosis and clearance of Ab peptide. Examples include
bapineuzumab (Wyeth), currently in Phase III clinical trial; c) rAGE
inhibitors- Amyloid binds to receptors for advanced glycated end
products (rAGE) at the blood brain barrier which contributes to neuronal
death. Blocking this amyloid-rAGE interaction can prevent amyloid
accumulation and neurotoxicity.
Decreasing Ab production- gamma
secretase inhibitors- Blocking the activity of g- secretase results in
prevention of cleavage of APP and hence the generation of Ab40 and Ab42.
Examples include Tarenflurbil, semagacestat. Beta-secretase is also a
promising target for inhibition of production of Ab40 and Ab42.
Targeting
Tau- Tau is another promising target whose aggregation, if inhibited,
results in reduction in the formation of neurofibrillary tangles.
Methylene blue has been shown to interfere with tau aggregation. A Phase
II study has been completed.
Metal chelation- The amoebicidal
drug, clioquinol, causes regression of amyloid deposits by chelating
with metal ions like copper and zinc which bind to amyloid thereby
preventing its dissolution. Chelation with such ions promotes
dissolution of the plaques.
Scope of peptides
Peptides
are increasingly being favoured as therapeutics for several diseases and
disorders because of lesser toxicity in vivo (non toxic metabolites)
and high specificity towards biomolecular targets (due to complex
tertiary structure). However, peptide administration has its own
troubles too, that is, they are highly susceptible to cleavage by
gastric enzymes and they may give rise to allergic responses. These
problems may be solved by replacing some amino acids with their
unnatural counterparts and by truncating the peptide to its smaller,
equally/more potent analogues, respectively. Peptides that are derived
from protein-protein interaction sites may serve as antagonists by
mimicking the properties of one of the interfaces and inhibiting the
interaction of the two binding partners. Development of the peptide
based ligand mimetics is usually based on knowledge of the amino acids
that are crucial to the contact site and binding.
General strategies to treat amyloidosis
Extensive
research is being directed towards exploring the activity of peptides
in the therapy of AD, mostly investigating various aspects of
pathogenesis mediated by the aggregated amyloid peptide and attempting
to counteract it with peptides or peptidomimetics.
Synthesis and evaluation of novel b-secretase inhibitors based on C-terminus pyridyl containing Phe-Ala pentapeptides.
Investigating
inhibition of catalytic production of H2O2 by the phage peptides (6-mer
and 15-mer) that bind to b-amyloid at a site which interacts with metal
ions.
Studies on Pr-IIGLa, a derivative of Ab31-34, as an
aggregation inhibitor and its further modification by incorporating a
highly polar amino acid such as arginine against the propionyl group in
order to decrease hydrophobicity (hence, the self aggregating capacity
and toxicity) giving rise to a new sequence, RIIGLa that has high
efficacy as an inhibitor of aggregation and toxic effects of Ab1-42
along with improved solubility.
Inhibition of Aß fibrillation and
destabilization of preformed fibrils by S-allyl-L-cysteine (SAC), a
water soluble organosulphur component present in garlic. SAC induces a
partially folded conformation of Ab which does not allow further
oligomerization. However, SAC may prevent the progression of AD by
multiple mechanisms in vivo.
Investigation of neuroprotective
effects of the tripeptide Ab32-34 having the sequence Ile-Gly-Leu (IGL).
It acts by blocking the inhibition of type II phosphatidylinositol
4-kinase (PI4KII) activity and the enhancement of glutamate toxicity
caused by Aß1-42.
Designing of newer b-sheet breaker peptides
such as LPYFD, an analogueueue of Soto’s peptide LPFFD by performing two
changes in order to increase binding affinity- (1) one phenylalanine
was replaced with tyrosine: the additional phenolic OH- group increases
the binding affinity; (2) the C-terminal carboxylate anion (-COO-) was
replaced with carboxamide (-CONH2) group to increase the binding
affinity. This pentapeptide binds to Ab1-42 in the 18-22 region (VFFAE).
Conclusions
With
increasing interest in exploring the value of peptides as drugs, it has
become possible to hope for finding a cure for AD, something that was
seemingly impossible earlier. The aforementioned sequences that show
potential activity against amyloidogenesis and its neurotoxic effects
can serve as motifs for the designing and synthesis of novel peptides
and peptidomimetics which may help cure Alzheimer’s Disease.
Rahul Jain is professor and Cheshta Kapoor is
third semester MS student in the Department of Medicinal Chemistry,
NIPER, S.A.S.Nagar, Mohali, Punjab.