Lukas Wanka

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occured before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146–156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice.

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac‐DGGLAG‐NH2, called P21, when administered peripherally, enhanced learning as well as both short‐term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Lipophilic Oligopeptides for Chemo- and Enantioselective Acyl Transfer Reactions onto Alcohols

Inspired by the extraordinary selectivities of acylases, we envisioned the use of lipophilic oligopeptidic organocatalysts for the acylative kinetic resolution/desymmetrization of rac- and meso-cycloalkane-1,2-diols. Here we describe in a full account the discovery and development process from the theoretical concept to the final catalyst, including scope and limitations. Competition experiments with various alcohols and electrophiles show the full potential of the employed oligopeptides. Additionally, we utilized NMR and IR-spectroscopic methods as well as computations to shed light on the factors responsible for the selectivity. The catalyst system can be readily modified to a multicatalyst by adding other catalytically active amino acids to the peptide backbone, enabling the stereoselective one-pot synthesis of complex molecules from simple starting materials.