Fellutamide B is a potent inhibitor of the Mycobacterium tuberculosis proteasome

Abstract

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.

Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation

“…2 It is also a strong inhibitor of the Mycobacterium tuberculosis proteasome. 3 Unfortunately, two different compounds have were named fellutamide C in the literature around the same time-frame. To resolve ambiguity between them, Singh’s fellutamide C structure 1c has been renamed in this work fellutamide E, an approach consistent with others.…”

Total Synthesis and Stereochemical Assignment of Nostosin B

“…Small peptide aldehydes had long been used as proteasome inhibitors, further development of these compounds as antibacterial, anticancer, or other therapeutic reagents have also been reported, e.g., fellutamide B was used to reveal the connection of proteasome inhibition and nerve growth factor (NGF) production, which could have potential for the treatment of neuronal injury and neurodegenerative diseases [15,16,17]. Herein, we report our total synthesis and stereochemical assignment of nostosin B.…”

Rational Design of Selective and Bioactive Inhibitors of the Mycobacterium tuberculosis Proteasome

“…5 This presumption has been validated by reports that Mtb 20S inhibitors, like null mutations in the proteasome gene, sensitize Mtb to nitric oxide. 3,6–9 This chemical validation gives credence to an unconventional pharmacological strategy in which small molecules are not used to kill Mtb , but to render it susceptible to the immune response.…”

“…3,6–9 Indeed, the 20S peptidases of Mtb and eukaryotes share a barrel-shaped α 7 β 7 β 7 α 7 structure and have a catalytic, N-terminal threonine residue. Though they are structurally related, the catalytic β-subunits in eukaryotes have three different isoforms exhibiting distinct substrate specificities, while those in the Mtb are identical.…”