Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (4 results)

  • Article
  • Peer Reviewed
UC Riverside Previously Published Works (2018)
Drawing on our recent success with reagent-less peptide-bond formation through serine-based assembly reactions in organic solvent, their range has been expanded to threonine and homoserine (an aspartic acid precursor) in the N-terminal peptide. Amino acid scope available at the assembly C-terminus includes bulky residues not amenable to classical ligation methods, such as cysteine-based NCL in aqueous media. The method was used to assemble a snakebite-toxin-neutralizing peptide from opossums.
    Cover page: Homoserine and Threonine Peptide AssemblyCreative Commons 'BY-NC-ND' version 4.0 license
    • Thesis
    • Peer Reviewed
    UC Riverside Electronic Theses and Dissertations (2017)

    Part one describes the synthesis and bioactivity of syrbactin derivatives. The syrbactins are a class of structurally similar natural products that were discovered to effectively induce apoptosis in various cancer cell lines through irreversible binding and inhibition of the constitutive proteasome. The success of proteasome inhibitors bortezomib and carfilzomib as cancer therapeutics has promoted further interest in the syrbactins. Previous work conducted by the Pirrung laboratory exploring the structure-activity relationship of syrbactin analogs has inspired the investigation into the synthesis of a unique set of syrbactin derivatives in efforts to create next-generation proteasome inhibitors with improved potency and enhanced overall efficacy. In this work, a novel set of syrbactin based derivatives have been proposed, synthesized, and the biological activities have been evaluated. Additionally, thiasyrbactin derivatives have been discovered to have unique properties resulting in rare and selective inhibition of the immunoproteasome. The immunoproteasome has been linked to a variety of diseases including various cancers, autoimmune, and neurodegenerative diseases, and is therefore, a novel therapeutic target.

    Part two describes the development of peptide assembly by ligation of hydroxyl amino acids threonine and homoserine with mildly activated esters. Many advances in the field of peptide chemistry have occurred allowing for the synthesis and bioevaluation of complex peptides and proteins. The development of native chemical ligation (NCL), a chemoselective cysteine-based peptide-coupling technique, provided a breakthrough in the chemical synthesis of peptides. Cysteine is one of the least abundant amino acids in natural peptides; thus, additional ligation methods based on other amino acids are essential. Recently, the Pirrung laboratory has developed a method of peptide assembly reacting β-hydroxylamines including serine, with activated esters to form amide bonds. This strategy mimics the mechanism of NCL via transesterification and subsequent acyl transfer to form a native peptide bond at the ligation site. In this work, peptide assembly with mildly activated esters has been successfully extended to the hydroxyl amino acids threonine and homoserine, expanding the scope of this ligation method. The utility of this method was further demonstrated by the synthesis of the opossum peptide, antivenom lethal toxin neutralizing factor-10 (LTNF-10).

      Cover page: I. Synthesis and Bioactivity of Novel Proteasome Inhibiting Syrbactins and II. Peptide Assembly by Ligation of Hydroxyl Amino Acids and Mildly Activated Esters
      • Article
      • Peer Reviewed
      UC Riverside Previously Published Works (2018)

      Background/aim

      Proteasome inhibition is a validated therapeutic strategy for the treatment of refractory and relapsed multiple myeloma (MM) and mantle cell lymphoma. We previously showed that thiasyrbactins (NAM compounds) are inhibitors with an affinity for the trypsin-like (T-L, β2) site of the constitutive proteasome, and more profoundly for the T-L site of the immunoproteasome.

      Materials and methods

      In this study, the biological activity of three NAM compounds was evaluated using four MM cell lines (ARD, U266, MM1R, and MM1S). We assessed the effect of (NAM-93, NAM-95, and NAM-105 on cell viability, as well as cell-based proteasomal activities, and determined the EC50 and Ki50 values, respectively.

      Results

      MM cells were most sensitive to NAM-93 with EC50 values <0.75 μM after 48 h of treatment. NAM-105 had a similar profile in most of the MM cells with EC50 values ranging between 0.42 and 3.02 μM. The level of inhibition of the proteasome T-L sub-catalytic activity in actively-growing MM cells was similar for NAM-93 and NAM-105. However, in each cell line, NAM-93 was more effective than NAM-105 at inhibiting overall trypsin-like sub-catalytic activity while NAM-105 was typically more effective at inhibiting overall chymotrypsin-like (CT-L, β5) sub-catalytic activity.

      Conclusion

      These results show for the first time the proteasome-targeted biological activity of thiasyrbactins in MM tumor cells.
        Cover page: Thiasyrbactins Induce Cell Death via Proteasome Inhibition in Multiple Myeloma Cells
        • Article
        • Peer Reviewed
        UC Riverside Previously Published Works (2018)
        A family of macrodilactam natural products, the syrbactins, are known proteasome inhibitors. A small group of syrbactin analogs was prepared with a sulfur-for-carbon substitution to enhance synthetic accessibility and facilitate modulation of their solubility. Two of these compounds surprisingly proved to be inhibitors of the trypsin-like catalytic site, including of the immunoproteasome. Their bound and free conformations suggest special properties of the thiasyrbactin ring are responsible for this unusual preference, which may be exploited to develop drug-like immunoproteasome inhibitors. These compounds show greater selectivity than earlier compounds used to infer phenotypes of immunoproteasome inhibition, like ONX-0914.
          Cover page: Immunoproteasome inhibition and bioactivity of thiasyrbactins.Creative Commons 'BY-NC-ND' version 4.0 license
          Top