20S Proteasome Inhibition: Designing Noncovalent Linear Peptide Mimics of the Natural Product TMC‐95A

Inhibition of Human and Yeast 20S Proteasome by Analogues of Trypsin Inhibitor SFTI-1

“…Further research [32] has indicated that TMC-95A inhibits the ChT-L, T-L and C-L activities of 20S proteasome with K i app (apparent K i constant) values of 1.1 n m , 0.81 µ m and 29 n m , respectively. Furthermore, less potent simplified cyclic [33], [34], non-constrained linear [35], [36] and dimerized linear mimics of TMC-95A [37], [38] have also been synthesized and analyzed. Blackburn et al [39], [40] screened a library of around 350 000 C - and N -terminally capped tripeptides derived from the unnatural amino acid S -homo-phenylalanine that potently and selectively inhibited the ChT-L activity of the mammalian and yeast 20S proteasomes.…”

Blockade of the malignant phenotype by β-subunit selective noncovalent inhibition of immuno- and constitutive proteasomes

“…In this orientation, the 4-CH 3 -phenyl group of molecule B1e could nicely fit into the hydrophobic and relatively large S1-specificity pocket and have favorable interactions with Met 45, an important amino acid of this subpocket. This orientation would thus mimic the P1-leucine side chain of the covalent bortezomib inhibitor co-crystallized with the human proteasome molecule or of the C -terminal benzylic group of compound A1b [11] and A2 [12] also co-crystallized with the proteasome. The piperazine group of B1e could have additional hydrophobic interactions and form several hydrogen bonds in the S2-S3 subsites.…”

“…A large variety of other covalent inhibitors of the cCP have been reported [8, 9] whereas noncovalent ones are less frequent. Some molecules contain a N -capped dipeptide backbone (compounds A1a-b, Figure 1B) [10, 11] or mimic the natural cyclic tripeptide TMC-95 (compound A2) [12–14] (Figure 1B). Recently reported noncovalent inhibitors are now essentially organic compounds [15–21] (compounds A3-A7, Figure 1B).…”

“…The constitutive β -subunits β 1, bearing the so-called caspase–like or post-acid activity (PA, often cleaves after acidic amino acids), β 2, bearing the trypsin-like activity (T-L, often cleaves after basic amino acids) and β 5 bearing the chymotrypsin-like activity (ChT-L, often cleaves after hydrophobic amino acids) are replaced in the iCP by three homologous subunits ( β 1i, LMP2; β 2i, MECL; β5i, LMP7). Of importance, small compounds interfering with one type of catalytic activity can also block the others (cross-react) as observed for instance for the TMC-95 mimic A2 (Figure 1B) [12–14] that binds to all three proteosomal active centers. Some compounds can cross-react between iCP and cCP and also between proteasomes of different species [8, 9, 29, 30].…”

Macrocyclic Proteasome Inhibitors

“…Again, structural studies of these compounds in complex with yeast 20S proteasome helped to clarify the structural basis of their inhibition potency. It seems as an optimized occupation of the substrate binding sites of the proteasome as well as the C-terminal group of these inhibitors play an important role for their observed potent inhibition [85]. The chemistry and biology of TMC-95s has been reviewed recently [86].…”