Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome

Add time:09/06/2019    Source:sciencedirect.com

Via high-throughput screening of a natural compound library, we have identified a lipopeptide aldehyde, fellutamide B (1), as the most potent inhibitor of the Mycobacterium tuberculosis (Mtb) proteasome tested to date. Kinetic studies reveal that 1 inhibits both Mtb and human proteasomes in a time-dependent manner under steady-state condition. Remarkably, 1 inhibits the Mtb proteasome in a single-step binding mechanism with Ki = 6.8 nM, whereas it inhibits the human proteasome β5 active site following a two-step mechanism with Ki = 11.5 nM and Ki∗ = 0.93 nM. Co-crystallization of 1 bound to the Mtb proteasome revealed a structural basis for the tight binding of 1 to the active sites of the Mtb proteasome. The hemiacetal group of 1 in the Mtb proteasome takes the (R)-configuration, whereas in the yeast proteasome it takes the (S)-configuration, indicating that the pre-chiral CHO group of 1 binds to the active site Thr1 in a different orientation. Re-examination of the structure of the yeast proteasome in complex with 1 showed significant conformational changes at the substrate-binding cleft along the active site. These structural differences are consistent with the different kinetic mechanisms of 1 against Mtb and human proteasomes.

We also recommend Trading Suppliers and Manufacturers of fellutamide A (cas 138682-08-3). Pls Click Website Link as below: cas 138682-08-3 suppliers

Prev:Solution phase synthetic approach to fellutamide B
Next:Neurotrophic peptide aldehydes: Solid phase synthesis of fellutamide B and a simplified analog)