| EPSRC Reference: |
GR/N08476/01 |
| Title: |
MOLECULAR RECOGNITION OF POTENT CYCLAM ANTIHIV AGENTS |
| Principal Investigator: |
Sadler, Professor P |
| Other Investigators: |
|
| Researcher Co-Investigators: |
|
| Project Partners: |
|
| Department: |
Sch of Chemistry |
| Organisation: |
University of Edinburgh |
| Scheme: |
Standard Research (Pre-FEC) |
| Starts: |
16 October 2000 |
Ends: |
15 October 2003 |
Value (£): |
173,366
|
| EPSRC Research Topic Classifications: |
| Biological & Medicinal Chem. |
Medical science & disease |
|
| EPSRC Industrial Sector Classifications: |
| Pharmaceuticals and Biotechnology |
No relevance to Underpinning Sectors |
|
| Related Grants: |
|
| Panel History: |
|
|
Summary on Grant Application Form |
|
The bicyclam AMD3100 is a potent antiHIV agent now on clinical trial. It has an unusual mechanism of action being active at the fusion/uncoating step. The CXCR4 coreceptor on the surface of T-lymphocytes has been identified as the target site. There is an urgent need to elucidate the nature of interactions between bicyclams and peptides and proteins and to investigate the possible role of chelated metal icons in such recognition processes. We propose to investigate the thermodynamics and kinetics of interactions between cyclams, bicyclams and their metal complexes (especially active metal ions such as Zn(ii) and Ni(II), and inactive Pd(II) and Pt(II)) and peptides related to extracellular loop 2 of CXCR4, including the recognition of specific cyclam conformations, NH H-bonding, and axial or equatorial peptide coordination to the metal. Novel syntheses will include 15N-labelling of AMD3100, heterobimetallic derivatives, and incorporation of fluorescent and redox linkers. 2D (1H, 15N) and other NMR studies will be complemented by molecular mechanics calculations, X-ray spectroscopy, and use of other appropriate techniques. Novel second generation bicyclams will be tested for antiviral activity in collaboration with Professor Erik De Clercq via participation in COST Action D8.
|
|
Key Findings |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
|
Potential use in non-academic contexts |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
|
Impacts |
|
| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
|
| Date Materialised |
|
|
|
|
Sectors submitted by the Researcher |
|
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
|
| Project URL: |
|
| Further Information: |
|
| Organisation Website: |
http://www.ed.ac.uk |