Structural Basis for a New Mechanism of Inhibition of H I V-1 Integrase Identified by Fragment Screening and Structure-Based Design
| Autor: | John Deadman, G. Paul Savage, Craig L. Francis, John H. Ryan, Thomas S. Peat, Jessica A. Smith, Dharshini Jeevarajah, Jonathan Coates, Janet Newman, Lisa Jane Winfield, Del Lucent, Giang Thanh Le, Neeranat Thienthong, Eric Dale Jones, David Ian Rhodes, Nick Vandegraaff |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Isatin
Crystallography Indoles Magnetic Resonance Spectroscopy Alkylation biology Mechanism (biology) HIV Infections Dioxoles General Medicine Computational biology Surface Plasmon Resonance Ligands Integrase Structure-Activity Relationship Biochemistry Catalytic Domain Drug Design HIV-1 biology.protein Hiv 1 integrase Structure based HIV Integrase Inhibitors Protein Binding |
| Zdroj: | Antiviral Chemistry and Chemotherapy. 21:155-168 |
| ISSN: | 2040-2066 |
| DOI: | 10.3851/imp1716 |
| Popis: | Background: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. Methods: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. Results: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme–fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. Conclusions: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|