No abstract

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.

No abstract

The cover feature picture shows new reblastatin derivatives obtained by a chemo‐biosemisynthetic approach with the corresponding aminobenzoic acid derivatives as starting building blocks. The fluoro and amino derivatives exerted high inhibitory activity on human and leishmania Hsp90, whereas the presence of an alkynyl substituent leads to selective activity towards Hsp90 from leishmania. The inhibitory activity was unraveled by using a novel protein microarray system with purified Hsp90 proteins and was further confirmed by cell‐based assays and ITC measurements. More information can be found in the full paper by C. Zeilinger, A. Kirschning et al. on page 562 in Issue 6, 2018 (DOI: 10.1002/cbic.201700616).