Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors

Bauder, Michael; Meyners, Christian; Purder, Patrick L.; Merz, Stephanie; Sugiarto, Wisely Oki; Voll, Andreas M.; Heymann, Tim; Hausch, Felix

doi:10.1021/acs.jmedchem.0c02195

Cited by 33 publications

(31 citation statements)

References 57 publications

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“…To explore the thermodynamic signature for the enhanced affinity of a-methyl-containing bicyclic [4.3.1] aza amides we used isothermal titration calorimetry (ITC) 13,31 (Table S4 †). The affinities measured with ITC were fully consistent with the FPassay data (Fig.…”

Section: Resultsmentioning

confidence: 99%

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

et al. 2021

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Section: Resultsmentioning

confidence: 99%

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

et al. 2021

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“…Of note is the protection of the peptide with residues 89–98 in FKBP51FK1 and, similarly, that with residues 53–71 in FKBP12. These span an α-helix (αB) containing, or being close to, a key interacting amino acid residue (Ile56 in FKBP12 and Ile87 in FKBP51FK1) that forms a strong hydrogen bond with both ligands through its amide nitrogen atom [ 49 , 52 , 53 , 54 ]. Furthermore, a very reactive tryptophan (based on both the inherent reactivity of the side chain toward oxidative labelling, and the direct observation, as shown in Figure 8 C) that is located within the binding pocket and directly exposed to solvent in the absence of a ligand is located in this region.…”

Section: Resultsmentioning

confidence: 99%

Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation

Nehls

Heymann

Meyners

et al. 2021

IJMS

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In order to understand protein structure to a sufficient extent for, e.g., drug discovery, no single technique can provide satisfactory information on both the lowest-energy conformation and on dynamic changes over time (the ‘four-dimensional’ protein structure). Instead, a combination of complementary techniques is required. Mass spectrometry methods have shown promise in addressing protein dynamics, but often rely on the use of high-end commercial or custom instruments. Here, we apply well-established chemistry to conformation-sensitive oxidative protein labelling on a timescale of a few seconds, followed by analysis through a routine protein analysis workflow. For a set of model proteins, we show that site selectivity of labelling can indeed be rationalised in terms of known structural information, and that conformational changes induced by ligand binding are reflected in the modification pattern. In addition to conventional bottom-up analysis, further insights are obtained from intact mass measurement and native mass spectrometry. We believe that this method will provide a valuable and robust addition to the ‘toolbox’ of mass spectrometry researchers studying higher-order protein structure.

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“…16j (Ziegler et al, 2020) and 19 (S)-Me (Pomplun et al, 2018) are both highly cell permeable (Gnatzy et al, 2021), excluding limited cell permeability as a reason for the lack of efficacy for the non-immunosuppressive FK506. Therefore, the lack of inhibitory effect of 16j (Pomplun et al, 2018) and 19 (S)-Me (Bauder et al, 2021) in all infection models may indicate a more important role of the FK506 calcineurin binding domain in the inhibition of coronavirus replication than for CsA.…”

Section: Discussionmentioning

confidence: 98%

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models

Berthold

Ma-Lauer

Chakraborty

et al. 2022

Front. Cell. Infect. Microbiol.

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RationaleHuman coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively.MethodsPrimary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication.ResultsBoth CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model.ConclusionThe immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

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Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors

Cited by 33 publications

References 57 publications

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides

Fenton-Chemistry-Based Oxidative Modification of Proteins Reflects Their Conformation

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models

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