Dihydrofolate reductase as a therapeutic target for infectious diseases: opportunities and challenges

Abstract

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.