ArticleThe Journal of biological chemistry2011
Phage display of tissue inhibitor of metalloproteinases-2 (TIMP-2): identification of selective inhibitors of collagenase-1 (metalloproteinase 1 (MMP-1)).
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Modifying inhibitor specificity for homologous enzymes by machine learning.The FEBS journal · 2026Article
- Extracellular vesicles delivering TIMP-2 modulate MMP-1, MMP-2, and MMP-9 expression in human lung adenocarcinoma A549 cells.Frontiers in pharmacology · 2026Article
- Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension.Biomolecules · 2024Article
- Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension.bioRxiv : the preprint server for biology · 2024Article
- Engineering metalloproteinase inhibitors: tissue inhibitors of metalloproteinases or antibodies, that is the question.Current opinion in biotechnology · 2024Review
- Exploring the Potential of Bioactive Peptides: From Natural Sources to Therapeutics.International journal of molecular sciences · 2024Review
- Computational design of matrix metalloprotenaise-9 (MMP-9) resistant to auto-cleavage.The Biochemical journal · 2023Article
- Designed Loop Extension Followed by Combinatorial Screening Confers High Specificity to a Broad Matrix MetalloproteinaseInhibitor.Journal of molecular biology · 2023Article
- Computational design of Matrix Metalloprotenaise-9 (MMP-9) resistant to auto-cleavage.bioRxiv : the preprint server for biology · 2023Article
- Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14.Scientific reports · 2023Article
- Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14.Research square · 2023Article
- The Repertoire of Tissue Inhibitors of Metalloproteases: Evolution, Regulation of Extracellular Matrix Proteolysis, Engineering and Therapeutic Challenges.Life (Basel, Switzerland) · 2022Review
- Peptides and Peptidomimetics as Inhibitors of Enzymes Involved in Fibrillar Collagen Degradation.Materials (Basel, Switzerland) · 2021Review
- Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics.Cells · 2020Review
- Quantitative mapping of binding specificity landscapes for homologous targets by using a high-throughput method.The Biochemical journal · 2020Article
- Review
- Directed evolution of the metalloproteinase inhibitor TIMP-1 reveals that its N- and C-terminal domains cooperate in matrix metalloproteinase recognition.The Journal of biological chemistry · 2019Article
- Targeting the MMP-14/MMP-2/integrin αThe Journal of biological chemistry · 2018Article
- Combinatorial engineering of N-TIMP2 variants that selectively inhibit MMP9 and MMP14 function in the cell.Oncotarget · 2018Article
- Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14.FEBS letters · 2018Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Tissue inhibitor of metalloproteinases-2 (TIMP-2) is a broad spectrum inhibitor of the matrix metalloproteinases (MMPs), which function in extracellular matrix catabolism. Here, phage display was used to identify variants of human TIMP-2 that are selective inhibitors of human MMP-1, a collagenase whose unregulated action is linked to cancer, arthritis, and fibrosis. Using hard randomization of residues 2, 4, 5, and 6 (L1) and soft randomization of residues 34-40 (L2) and 67-70 (L3), a library was generated containing 2 × 10(10) variants of TIMP-2. Five clones were isolated after five rounds of selection with MMP-1, using MMP-3 as a competitor. The enriched phages selectively bound MMP-1 relative to MMP-3 and contained mutations only in L1. The most selective variant (TM8) was used to generate a second library in which residues Cys(1)-Gln(9) were soft-randomized. Four additional clones, selected from this library, showed a similar affinity for MMP-1 as wild-type TIMP-2 but reduced affinity for MMP-3. Variants of the N-terminal domain of TIMP-2 (N-TIMP-2) with the sequences of the most selective clones were expressed and characterized for inhibitory activity against eight MMPs. All were effective inhibitors of MMP-1 with nanomolar K(i) values, but TM8, containing Ser(2) to Asp and Ser(4) to Ala substitutions, was the most selective having a nanomolar K(i) value for MMP-1 but no detectable inhibitory activity toward MMP-3 and MMP-14 up to 10 μM. This study suggests that phage display and selection with other MMPs may be an effective method for discovering tissue inhibitor of metalloproteinase variants that discriminate between specified MMPs as targets.
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Registered trials
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.