ArticleProceedings of the National Academy of Sciences of the United States of America2011
Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 103 citations in OpenAlex.
- Bridging mechanism and design: modern medicinal chemistry approaches to thymidylate synthase inhibitors.RSC advances · 2026Review
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- Enhanced anticancer effect of thymidylate synthase dimer disrupters by promoting intracellular accumulation.Frontiers in pharmacology · 2024Article
- Identification and functional validation of SRC and RAPGEF1 as new direct targets of miR-203, involved in regulation of epidermal homeostasis.Scientific reports · 2023Article
- Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.ACS pharmacology & translational science · 2023Article
- Molecular recognition of SARS-CoV-2 spike protein with three essential partners: exploring possible immune escape mechanisms of viral mutants.Journal of molecular modeling · 2023Article
- Peptides for diagnosis and treatment of ovarian cancer.Frontiers in oncology · 2023Review
- Article
- Convenient Synthesis ofACS omega · 2022Article
- Peptide therapeutics in the management of metastatic cancers.RSC advances · 2022Review
- Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1.Journal of medicinal chemistry · 2022Article
- Article
- Folic Acid-Peptide Conjugates Combine Selective Cancer Cell Internalization with Thymidylate Synthase Dimer Interface Targeting.Journal of medicinal chemistry · 2021Article
- An Update on the Potential Roles of E2F Family Members in Colorectal Cancer.Cancer management and research · 2021Review
- Targeting the TS dimer interface in bifunctional Cryptosporidium hominis TS-DHFR from parasitic protozoa: Virtual screening identifies novel TS allosteric inhibitors.Bioorganic & medicinal chemistry letters · 2020Article
- A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells.International journal of molecular sciences · 2020Article
- Safeguarding intestine cells against enteropathogenicProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions.AIMS microbiology · 2020Article
- Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth.Molecules (Basel, Switzerland) · 2019Article
- Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors.Molecules (Basel, Switzerland) · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The "LR" peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.