Bibliographic Details
| Title: |
Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth |
| Authors: |
Salvatore Pacifico, Matteo Santucci, Rosaria Luciani, Puneet Saxena, Pasquale Linciano, Glauco Ponterini, Angela Lauriola, Domenico D’Arca, Gaetano Marverti, Remo Guerrini, Maria Paola Costi |
| Source: |
Molecules, Vol 24, Iss 19, p 3493 (2019) |
| Publisher Information: |
MDPI AG, 2019. |
| Publication Year: |
2019 |
| Collection: |
LCC:Organic chemistry |
| Subject Terms: |
cyclic peptides, enzyme inhibition, thymidylate synthase inhibitors, allosteric inhibitors, anticancer agents, ovarian cancer, Organic chemistry, QD241-441 |
| More Details: |
Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify anti-TS drugs with new modes of action and able to overcome platinum drug resistance in ovarian cancer, octapeptides with a new allosteric inhibition mechanism were identified as cancer cell growth inhibitors that do not cause TS overexpression. To improve the biological properties, 10 cyclic peptides (cPs) were designed from the lead peptides and synthesized. The cPs were screened for the ability to inhibit recombinant human thymidylate synthase (hTS), and peptide 7 was found to act as an allosteric inhibitor more potent than its parent open-chain peptide [Pro3]LR. In cytotoxicity studies on three human ovarian cancer cell lines, IGROV-1, A2780, and A2780/CP, peptide 5 and two other cPs, including 7, showed IC50 values comparable with those of the reference drug 5-fluorouracil, of the open-chain peptide [d-Gln4]LR, and of another seven prolyl derivatives of the lead peptide LR. These promising results indicate cP 7 as a possible lead compound to be chemically modified with the aim of improving both allosteric TS inhibitory activity and anticancer effectiveness. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1420-3049 |
| Relation: |
https://www.mdpi.com/1420-3049/24/19/3493; https://doaj.org/toc/1420-3049 |
| DOI: |
10.3390/molecules24193493 |
| Access URL: |
https://doaj.org/article/61da817c7a194f56a082b000a4c8c452 |
| Accession Number: |
edsdoj.61da817c7a194f56a082b000a4c8c452 |
| Database: |
Directory of Open Access Journals |
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