An emerging common feature of the age-associated neurodegenerative disorders like Alzheimer's disease (AD)
and Creutzfeldt-Jakob disease (CJD) is the ability of many disease-associated protein aggregates to induce conversion of a
normal counterpart conformer leading to an acceleration of disease progression. Curative pharmacotherapy has not been
achieved so far despite successes in elucidating pathomechanisms. Here, we review the pharmaceutical strategy of generating
hybrid compounds, i.e. compounds consisting of several independently acting moieties with synergistic effects, on
key molecular players in AD and CJD.
For prion diseases, we review hybrid compounds consisting of two different heterocyclic compounds, their synergistic effects
on prion replication in a cell culture model and their ability to prolong survival of experimentally prion-infected
mice in vivo. While a combination therapy of several antiprion compounds including quinacrine, clomipramine, simvastatin
and tocopherol prolonged survival time to 10-25%, administration of hybrid compound quinpramine alone, a chimera
of acridine and iminodibenzyl scaffolds, led to 10% survival time extension.
For AD, we review a hybrid compound consisting of an A recognizing D-peptide fused to a small molecule -sheet
breaker, an aminopyrazole. This molecule was able to diminish A oligomers in cell culture and significantly decrease
synaptotoxicity as measured by miniature excitatory postsynaptic responses in vitro.
Hybrid compounds can dramatically increase potency of their single moieties and lead to novel functions when they act in
a simultaneous or sequential manner thereby revealing synergistic properties. Their systematic generation combining different
classes of compounds from peptides to small molecules has the potential to significantly accelerate drug discovery.