The Interplay between Mutasynthesis and Semisynthesis: Generation and Evaluation of an Ansamitocin Library

Eichner, Simone; Knobloch, Tobias; Floss, Heinz G.; Fohrer, Jörg; Harmrolfs, Kirsten; Hermane, Jekaterina; Schulz, Anne; Sasse, Florenz; Spiteller, Peter; Taft, Florian; Kirschning, Andreas

doi:10.1002/anie.201106249

Cited by 39 publications

(32 citation statements)

References 52 publications

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“…The cyclophilin inhibitor NVP018 was generated using a combination of semisynthetic and bioengineering methods. These are frequently used independently, but in the past have been less commonly used together ( Kennedy, 2008 , Eichner et al., 2012 ). This enabled a combinatorial approach to NP drug discovery and led to the selection of NVP018, a compound with more potent cyclophilin inhibition, antiviral potency versus HBV, HCV, and HIV-1, and reduced off-target transporter inhibition compared with the parent compound, sanglifehrin A.…”

Section: Discussionmentioning

confidence: 99%

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

Hansson

Moss

Bobardt

et al. 2015

Chemistry & Biology

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Summary Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent, high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed non-ribosomal peptide/polyketide origin in order to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of HBV, HCV and HIV-1 replication, shows minimal inhibition of major drug transporters and has a high barrier to generation of both HCV and HIV-1 resistance.

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Section: Discussionmentioning

confidence: 99%

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

Hansson

Moss

Bobardt

et al. 2015

Chemistry & Biology

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“…In a subsequent in vivo whole cell biocatalytic approach (Fig. 1B), we also investigate the production of beauvericins by mutational biosynthesis (MBS) [14][15][16][17] using a KIVR knockout strain of B. bassiana (B. bassiana kivr À ) 12 or an E. coli strain expressing BbBEAS (E. coli bbBeas…”

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confidence: 99%

In vitro chemoenzymatic and in vivo biocatalytic syntheses of new beauvericin analogues

et al. 2012

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“…This approach allowed us to determine the binding of fluorescence‐labelled ATP (Cy3‐ATP) as well as putative inhibitors that address the ATP binding site (Figure , bottom) and to carry out displacement measurements between ATP and the potential inhibitors . With this system to hand, we assayed the HsHsp90 and LbHsp90 inhibitory activities of new reblastatin derivatives and also of known reblastatin derivatives, as well as those of classical Hsp inhibitors such as radicicol, novobiocin and celastrol (Table ) . Concentrations were set at 500 n m against HsHsp90 and LbHsp90.…”

Section: Resultsmentioning

confidence: 99%

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

Mohammadi-Ostad-Kalayeh

Stahl

Scheper

et al. 2018

ChemBioChem

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Thirteen new reblastatin derivatives, with alkynyl, amino and fluoro substituents on the aromatic ring, were prepared by a chemo-biosynthetic approach using an AHBA(-) mutant strain of Streptomyces hygroscopicus, the geldanamycin producer. The inhibitory potencies of these mutaproducts and of an extended library of natural products and derivatives were probed with purified heat shock proteins (Hsps), obtained from Leishmania braziliensis (LbHsp90) as well as from human sources (HsHsp90). We determined the activities of potential inhibitors by means of a displacement assay in which fluorescence-labelled ATP competes for the ATP binding sites of Hsps in the presence of the inhibitor in question. The results were compared with those of cell-based assays and, in selected cases, of isothermal titration calorimetry (ITC) measurements. In essence, reblastatin derivatives are also able to bind effectively to the ATP-binding site of LbHsp90, and for selected derivatives, moderate differences in binding to LbHsp90 and HsHsp90 were encountered. This work demonstrates that parasitic heat shock proteins can be developed as potential pharmaceutical targets.

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The Interplay between Mutasynthesis and Semisynthesis: Generation and Evaluation of an Ansamitocin Library

Cited by 39 publications

References 52 publications

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection

In vitro chemoenzymatic and in vivo biocatalytic syntheses of new beauvericin analogues

Heat Shock Proteins Revisited: Using a Mutasynthetically Generated Reblastatin Library to Compare the Inhibition of Human and Leishmania Hsp90s

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