Alzheimer’s disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks. Peptide-based aggregation inhibitors hold significant promise for future AD therapy owing to their high selectivity, effectiveness, low toxicity, good tolerance, low accumulation in tissues, high chemical and biological diversity, possibility of rational design, and highly developed methods for analyzing their mode of action, proteolytic stability (modified peptides), and blo...

Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer’s Disease

Learning from the past and looking to the future: Emerging perspectives for improving the treatment of psychiatric disorders

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis “probable AD” can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-β peptide (Aβ). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Aβ play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs.

Peptides for therapy and diagnosis of Alzheimer's disease.

Sulfonamide derivatives as potential anti-cancer agents and their SARs elucidation.

Synthesis, characterization and biological evaluation of tertiary sulfonamide derivatives of pyridyl-indole based heteroaryl chalcone as potential carbonic anhydrase IX inhibitors and anticancer agents.

Increasing the potency of synthesized drugs has been a stepwise process accomplished by progressively modifying the chemical scaffold of a single parent lead compound. To date, there has been no basis for thinking that the combination of pharmacological effects of independently acting drugs could be achieved beyond mere simultaneous administration. We reasoned that if the target molecule of two independent classes of drugs was the same, chemical synthesis of a hybrid compound where these drugs presented moieties within one molecule might yield synergistic effects; that is, a new quality might emerge that would be more than the sum of the singlemoiety compounds. Such multifunctional hybrid compounds that assign different functions to its different moieties to achieve a synergistic pharmacodynamic effect have successful predecessors in nature: for example, bleomycin is a natural compound with three different moieties acting in concert to cleave DNA.

Combining independent drug classes into superior, synergistically acting hybrid molecules.

Gesteigerte Wirksamkeit durch Synergismus: Verknüpfung unabhängiger Wirkstoffklassen zu Hybridsubstanzen

Determining Aβ levels in body fluids remains a powerful tool in the diagnostics of Alzheimer's disease. This report delineates a new supramolecular strategy which increases the affinity of antibodies towards Aβ to make diagnostic procedures more sensitive. A monoclonal antibody IC16 was generated to an N-terminal epitope of Aβ and the variable regions of the heavy and light chains were cloned as a recombinant protein (scFv). A 6 × histidine tag was fused to the C-terminus of IC16-scFv allowing hybridization with a small organic β-sheet binder via Ni-NTA complexation. On the other hand, a multivalent nitrilotriacetic acid (NTA)-equipped trimeric aminopyrazole (AP) derivative was synthesized based on a cyclam platform; and experimental evidence was obtained for efficient Ni2+-mediated complex formation with the histidine-tagged antibody species. In a proof of principle experiment the hybrid molecule showed a strong increase in affinity towards Aβ. Thus, the specific binding power of recombinant antibody fragments to their β-sheet rich targets can be conveniently enhanced by non-covalent hybridization with small organic β-sheet binders.

/pdf/hybridization-of-an-ab-specific-antibody-fragment-with-3d780jakag.pdf

Hybridization of an Aβ-specific antibody fragment with aminopyrazole-based β-sheet ligands displays striking enhancement of target affinity

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Combining independent drug classes into superior, synergistically acting hybrid molecules.

Gesteigerte Wirksamkeit durch Synergismus: Verknüpfung unabhängiger Wirkstoffklassen zu Hybridsubstanzen

Hybridization of an Aβ-specific antibody fragment with aminopyrazole-based β-sheet ligands displays striking enhancement of target affinity