Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges.
Infectious diseases caused by parasites continue to take a massive toll on human health in the poor regions of the world. Filling the anti-infective drug-discovery pipeline has never been as challenging as it is now. The organisms responsible for these diseases have interesting biology with many potential biochemical targets. Inhibition of metabolic enzymes has been established as an attractive strategy for anti-infectious drug development. In this field, dihydrofolate reductase (DHFR) is an important enzyme in nucleic and amino acid synthesis and an extensively studied drug target over the past 50 years. The challenges for novel DHFR inhibition-based chemotherapeutics for the treatment of infectious diseases are now focused on overcoming the resistance problem as well as cost-effectiveness. Each year, the large number of literature citations attest the continued popularity of DHFR. It becomes truly the 'enzyme of choice for all seasons and almost all reasons'. Herein, we summarize the opportunities and challenges in developing novel lead based on this target.
Medicinal & Process Chemistry Division, Central Drug Research Institute (CSIR), Lucknow 226001, India.
Moni
M
Sharma
Prem M S
PM
Chauhan
D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D003141:Communicable Diseases / Q000188:drug therapy*; D004352:Drug Resistance, Microbial; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010271:Parasites / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism
D000890:Anti-Infective Agents; D000962:Antimalarials; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase; C030986:pyrimidine