Target protein

Summary

Target proteins are functional biomolecules that are addressed and controlled by biologically active compounds. They are used in the processes of transduction, transformation and conjugation. The identification of target proteins, the investigation of signal transduction processes and the understanding of their interaction with ligands are key elements of modern biomedical research. Since the interaction with target proteins is the molecular origin of most drugs, their particular importance for molecular biology, molecular pharmacy and pharmaceutical sciences is obvious. Target proteins control the action and the kinetic behavior of drugs within the organism. The elucidation of structure, conformational signaling and catalytic properties of particular target proteins facilitates a rational design of drugs and biotechnological processes. Known as biologicals, target proteins can also be drugs by themselves when their modification and formulation is emphasized within the pharmaceutical s

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Neurons are arranged in networks in which they communicate between each other by the means of synapses. Synaptic transmission can undergo activity-dependent and short-lived changes in strength, known as short-term synaptic plasticity. Short-term plasticity is an important mechanism for neural networks in living organisms, which plays a role in adaptation to sensory inputs and information processing. One of the interesting forms of short-term enhancement in transmitter release is post-tetanic potentiation (PTP). PTP is generated upon repetitive activity of the synapse and lasts tens of seconds to minutes. A more detailed understanding of the molecular mechanisms of short-term plasticity will be helpful to understand information processing in neural networks. Here, I studied the cellular and molecular basis of post-tetanic potentiation at the calyx of Held model synapse. Pharmacological inhibition of conventional protein kinase C (cPKC) isoforms resulted in a near- complete block of PTP. This showed that cPKC dependent phosphorylation of a target presynaptic protein is a key process underlying PTP. Upon inhibition of phosphatases by calyculin, PTP was remarkably prolonged, by the suppression of dephosphorylation. By expressing a FRET (Fluorescence Resonance Energy Transfer) based PKC activity probe, I obtained independent evidence for transient activation of cPKC during PTP. This refers to a transient phosphorylation/dephosphorylation, which underlies the short-term changes in the release probability during PTP. To investigate the target protein, which becomes phosphorylated by PKC during PTP, I studied phosphorylation of the presynaptic protein Munc18-1. By establishing a virus-mediated in vivo gene-replacement approach using floxed Munc18-1 mice, we replaced endogenous Munc18-1 with phosphorylation-deficient form of Munc18-1. I showed that in the nerve terminals expressing the phosphorylation deficient form of Munc18-1, PTP was strongly suppressed as compared to the wild type form of Munc18-1. This PhD thesis work proposes a molecular model for PTP in which a transient phosphorylation/dephosphorylation of Munc18-1 by conventional PKCs and phosphatases, respectively modulates the calcium sensitivity of vesicle fusion and determines the kinetics of PTP.

EPFL2013

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis

François Louis Mouvet, Ursula Röthlisberger

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH2-OXA), ruthenocene-containing (Rc-CH2-OXA) and benzene-containing (Ph-CH2-OXA) OXA derivatives. These derivatives showed excellent in vitro activity against bothSchistosoma mansonilarvae and adult worms andS. haematobiumadult worms, and were also active in vivo against adultS. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies onS. haematobiumand juvenileS. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity onS. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.

WILEY-V C H VERLAG GMBH2020

Introducing tolerance to foreign and partly foreign proteins by erythrocyte binding and artificial glycosylations

Kym Lorenz Brünggel

Over the last few years, protein drugs have steadily gained importance in the clinic. Compared to small molecule drugs, protein drugs are taken up by antigen presenting cells, which degrade the proteins into peptides that are then presented on major histocompatability complex I and II to CD8+ respectively CD4+ T-cells. CD4+ T-cells are then able to activate B-cells, which upon activation will produce anti-drug antibodies. While anti-drug antibodies have mostly been viewed as a safety risk leading to drug injection related side effects, they have recently been proven to diminish the efficacy of the treatment. High antibody titers against Humira, a clinically approved monoclonal antibody used to treat rheumatoid arthritis, have been associated with low serum drug concentration and high disease activity score, ultimately leading to treatment failure. Two approaches to induce tolerance were developed in the Hubbell lab. One approach utilizes protein variants that are designed to bind to circulating erythrocytes. As 1 % of erythrocytes undergo apoptosis each day and are taken up by antigen presenting cells, along with the bound protein, they are presented to the immune system in a non-inflammatory tolerogenic fashion. Immunological tolerance is thereby induced against the apoptotic erythrocyte debris and the associated bound protein. The second approach uses synthetic glucose, galactose or mannose polymers conjugated to the target protein. The polymers target C-type lectins, which are known to clear apoptotic debris, leading to presentation of the protein by hepatic antigen presenting cells in a tolerogenic liver microenvironment. This thesis investigates the potential of these approaches to induce tolerance towards protein drugs. Arylsulfatase B was used as a model protein to investigate the potential of tolerance induction by targeting circulating erythrocytes, as 97% of patients receiving arylsulfatase B develop anti-drug antibodies. An erythrocyte binding variant of arylsufatase B was created by chemically conjugating the erythrocyte binding peptide ERY1 to arylsulfatse B. In mice receiving two doses of ERY1-arylsulfatase B one week apart followed by weekly doses of arylsulfatase B a significant delay of four week in the production of anti-drug Antibodies was found when compared to mice receiving weekly doses of only arylsulfatase B. To investigate the ability of synthetic glyco-polymers to induce tolerance towards protein drugs we used asparaginase as model protein. Between 37.5 % to 75% of patients treated with asparaginase develop anti-drug antibodies. Administering three intravenous injections of asparaginase-conjugated to glucose polymers before eight weeks of treatment with asparaginase significantly reduced anti-drug antibody titers by a factor of 125 when compared to animals only receiving eight weeks of treatment with asparaginase. Three pre-injections with asparaginase conjugated to the galactose or mannose polymer led to a reduction in anti-drug antibody titers by a factor of 12 respectively 400 after 5 weeks of treatment with asparaginase when compared to mice receiving only asparaginase for 5 weeks. These results indicates that synthetic glyco polymers, especially mannose and glucose based ones, are able to induce long term tolerance towards asparaginase. Synthetic glucose and mannose polymers therefore represent an excellent molecular approach to induce tolerance towards protein drugs.

EPFL2018

EPFL2013

Introducing tolerance to foreign and partly foreign proteins by erythrocyte binding and artificial glycosylations

Kym Lorenz Brünggel

EPFL2018