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Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance. [ABSTRACT FROM AUTHOR]

Acquired resistance to drugs that modulate specific protein functions, such as the human proteasome, presents a significant challenge in targeted therapies. This underscores the importance of devising new methodologies to predict drug binding and potential resistance due to specific protein mutations. In this work, we conducted an extensive computational analysis to ascertain the effects of selected mutations (Ala49Thr, Ala50Val, and Cys52Phe) within the active site of the human proteasome. Specifically, we sought to understand how these mutations might disrupt protein function either by altering protein stability or by impeding interactions with a clinical administered drug. Leveraging molecular dynamics simulations and molecular docking calculations, we assessed the effect of these mutations on protein stability and ligand affinity. Notably, our results indicate that the Cys52Phe mutation critically impacts protein-ligand binding, providing valuable insights into potential proteasome inhibitor resistance.

Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8–38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC50 values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes.

A novel series of non-peptide proteasome inhibitors (PIs) that act on chymotrypsin-like (ChT-L) of the proteasome were developed. These PIs bearing 4-aromatic sulfonyl naphthalene-based scaffold and Leu-boronic moiety as covalent bonding group displayed far better activity than PI-8182 for inhibiting ChT-L in preliminary biological activity test. The results showed that 2a (IC 50  = 6.942 μM, MCF-7) and 2c (IC 50  = 6.905 μM, MCF-7) displayed higher anti-proliferative activities than Bortezomib (IC 50  = 18.37 μM, MCF-7) under our experimental conditions. Furthermore, in the microsomal stability assay, 2a demonstrated excellent metabolic stability profiles with 56% remaining after 40 min, as compared to Bortezomib of which approximately 30% was remaining. The compounds 2a , 2c emerged as promising lead compounds for the development of novel non-peptide boronate PIs. [ABSTRACT FROM AUTHOR]

Abstract: Eighteen novel spin-labeled 18β-glycyrrhetinic acid (GA) derivatives were designed, synthesized, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU-145, KB and KBvin). Most of the derivatives showed more significant cytotoxicity than that of the parent compound GA. The best compound, 6j, with a tryptophan amino moiety and piperidine nitroxyl radical showed GI50 values of 13.7–15.0μM, and was fivefold more potent than GA. In a mechanism of action study, compound 7a was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings support further optimization efforts based on 18β-GA as a lead compound to develop potential anticancer drug candidates. [Copyright &y& Elsevier]

Nostocyclopeptides (Ncps) are a small class of bioactive nonribosomal peptides produced solely by cyanobacteria of the genus Nostoc. In the current work, six Ncps were isolated from Nostoc edaphicum strain CCNP1411. The bioactivity of these compounds was tested in vitro against 20S proteasome, a proteolytic complex that plays an important role in maintaining cellular proteostasis. Dysfunction of the complex leads to many pathological disorders. The assays indicated selective activity of specific Ncp variants. For two linear peptide aldehydes, Ncp-A2-L and Ncp-E2-L, the inhibitory effects on chymotrypsin-like activity were revealed, while the cyclic variant, Ncp-A2, inactivated the trypsin-like site of this enzymatic complex. The aldehyde group was confirmed to be an important element of the chymotrypsin-like activity inhibitors. The nostocyclopeptides, as novel inhibitors of 20S proteasome, increased the number of natural products that can be considered potential regulators of cellular processes. [ABSTRACT FROM AUTHOR]

Abstract: Fourteen naphthoquinone derivatives (1–14) were designed based on a putative proteasome inhibitor PI-083. These compounds were synthesized and evaluated against A549, DU145, KB, and KBvin tumor cell lines. Six compounds (2, 4, 8, 9, 10, and 13) showed antiproliferative activities comparable to that of PI-083. Among them, compound 8 was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings endorse further optimization efforts based on this structural phenotype to develop potential anticancer drug candidates. [Copyright &y& Elsevier]