Award details

To explore the potential of peptidic natural products, and their synthetic analogues, for pest control.

Reference	BBS/E/C/00051535
Principal Investigator / Supervisor	Dr Bhupinder Pall Singh Khambay
Co-Investigators / Co-Supervisors
Institution	Rothamsted Research
Department	Rothamsted Research Department
Funding type	Research
Value (£)	73,012
Status	Completed
Type	Institute Project
Start date	01/04/1997
End date	31/03/1999
Duration	24 months

Abstract

This is a collaborative project, involving the University of Portsmouth (UP), University of Sussex (US), University of London (UL) and University of Belfast (UB), and with PUs 235 and 210 at Rothamsted. Lead compounds which are peptidic in nature are selected from RO 51562 for further evaluation under this RO. Such compounds are highly effective, usually at picomolar concentrations, and consequently offer a potentially rich source of novel insect control agents. However, in practice, their usefulness is limited by rapid metabolism, poor transport properties and cost of synthesis. This programme aims to address these limitations through synthesis of analogues which still retain high levels of insecticidal activity. Such analogues may include modification of the side- chain groups (eg alkylation of the -OH group of tyrosine) or replacement of selected peptidic bonds with isosteres which retain the overall geometry (eg - CH=CH- for - CO-NH- bond). Both types of modifications increase lipophilicity and metabolic stability and are aimed at eliciting a prolonged biological response in insects. This program entails using established organic synthetic methodology, which often requires some modification to achieve the required transformations in acceptable yields. Compounds are tested in specialist in vitro screens (at US, UL and UB) and their physical properties (PU 233) and transcuticular penetration rates (at UP) measured to establish structure- activity relationships. The overall aim is to identify new chemistries for the development of novel pest control agents and to underpin studies aimed at understanding their role in the organism producing them. Under this programme, insect neropeptides will continue to be examined by the SAR approach adopted in prevoius years. The on going programme on FLRFamide analogues will be consolidated and if possible, will be extended to include mammalian systems. This will be dependent on the outcome of a grant application. Work on the diuretic peptide, achetakinin I, will be consolidated and submitted for publication. Newer collaborations are continually being sought to extend the studies to other target molecules. Work begun on semi-synthesis of destruxin analogues with variations in the hydroxy acid side-chain will continue. Such variations will include substituted olefins and acetylenes. A rate limiting step in the progress of the Ph.D. work (with UP) has been the use of solution based methods for the construction of the cyclic depsipeptides. A new Ph.D. project to begin early in1998, also with UP, will focus on the use of solid phase methods for the synthesis of destruxins and their analogues. In addition, possible sites for isosteric bond replacement in the destruxins will be selected and appropriate isosteric bond containing building blocks will constructed for incorporation into the full destruxin motif. Sources of external funding to help support this work and further our collaboration with the University of Montpellier will continue to be sought. 2 2. Depending on the outcome of biological evaluation of the Colorado beetle dipeptide (RO 051562) an SAR programme will be initiated. Aspects to be examined will include substitution of the glutamyl residue with other proteinaceous amino acids, examination of the role of the diene side chain through synthesis of other unsaturated side chain containing amino acids and incorporation into the dipeptide, capping of the amino and carboxylic acid groups and introduction of isosteric bond replacements. Funding will be sought to support this work and also to investigate possible modes of action of the dipeptide. 3 3. Papers on FMRFamide and achetakinin I currently being drafted will be submitted.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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