AI Article Synopsis
- Peptides face challenges as drugs due to quick breakdown by enzymes and inability to enter cells easily.
- A new series of modified peptides with four-membered rings were developed to improve their stability and tested against the human 20S proteasome, resulting in 12 effective compounds.
- One compound, named 73, showed strong activity against multiple myeloma cell lines and demonstrated long-lasting effects in the body, making it a promising candidate for future drug development.
Article Abstract
Peptides have limitations as active pharmaceutical agents due to rapid hydrolysis by proteases and poor cell permeability. To overcome these limitations, a series of peptidyl proteasome inhibitors embedded with four-membered heterocycles were designed to enhance their metabolic stabilities. All synthesized compounds were screened for their inhibitory activities against human 20S proteasome, and 12 target compounds displayed potent efficacy with IC values lower than 20 nM. Additionally, these compounds exhibited strong anti-proliferative activities against multiple myeloma (MM) cell lines (MM1S: 72, IC = 4.86 ± 1.34 nM; RPMI-8226: 67, IC = 12.32 ± 1.44). Metabolic stability assessments of SGF, SIF, plasma and blood were conducted, and the representative compound 73 revealed long half-lives (Plasma: T = 533 min; Blood: T > 1000 min) and good proteasome inhibitory activity in vivo. These results suggest that compound 73 serve as a lead compound for the development of more novel proteasome inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bioorg.2023.106626 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!