Abstract
Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.
Keywords: Antimalarials, malaria, purines, pyrimidines, transition state analogues, immucillins, Chemotherapeutic and vector control, mosquito vectors, intraerythrocytic growth phase, purine and pyrimidine metabolic pathways, enzymatic transition state analysis, purine and pyrimidine metabolism, drug discovery has, unprecedented affinity specificity, Transition state analogue design
Current Topics in Medicinal Chemistry
Title: Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum
Volume: 11 Issue: 16
Author(s): Maria Belen Cassera, Yong Zhang, Keith Z. Hazleton and Vern L. Schramm
Affiliation:
Keywords: Antimalarials, malaria, purines, pyrimidines, transition state analogues, immucillins, Chemotherapeutic and vector control, mosquito vectors, intraerythrocytic growth phase, purine and pyrimidine metabolic pathways, enzymatic transition state analysis, purine and pyrimidine metabolism, drug discovery has, unprecedented affinity specificity, Transition state analogue design
Abstract: Malaria is a leading cause of morbidity and mortality in the tropics. Chemotherapeutic and vector control strategies have been applied for more than a century but have not been efficient in disease eradication. Increased resistance of malaria parasites to drug treatment and of mosquito vectors to insecticides requires the development of novel chemotherapeutic agents. Malaria parasites exhibit rapid nucleic acid synthesis during their intraerythrocytic growth phase. Plasmodium purine and pyrimidine metabolic pathways are distinct from those of their human hosts. Thus, targeting purine and pyrimidine metabolic pathways provides a promising route for novel drug development. Recent developments in enzymatic transition state analysis have provided an improved route to inhibitor design targeted to specific enzymes, including those of purine and pyrimidine metabolism. Modern transition state analogue drug discovery has resulted in transition state analogues capable of binding to target enzymes with unprecedented affinity and specificity. These agents can provide specific blocks in essential pathways. The combination of tight binding with the high specificity of these logically designed inhibitors, results in low toxicity and minor side effects. These features reduce two of the major problems with the current antimalarials. Transition state analogue design is being applied to generate new lead compounds to treat malaria by targeting purine and pyrimidine pathways.
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Cite this article as:
Belen Cassera Maria, Zhang Yong, Z. Hazleton Keith and L. Schramm Vern, Purine and Pyrimidine Pathways as Targets in Plasmodium falciparum, Current Topics in Medicinal Chemistry 2011; 11 (16) . https://dx.doi.org/10.2174/156802611796575948
DOI https://dx.doi.org/10.2174/156802611796575948 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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