Newly Discovered Protein May Hold Key to Better Drugs for Neglected Diseases

Researchers in the University of Dundee have discovered a new method of activating drugs to combat visceral leishmaniasis. The discovery could lead to better treatments for neglected tropical diseases.

Visceral leishmaniasis, a vector-borne disease afflicting parts of Asia, Africa and South America, is known to be the second biggest killer after malaria. Approximately 400,000 new cases are reported every year, with an estimated 40,000 deaths annually.

No vaccines are available and current treatments such as miltefosine and liposomal amphotericin B, which are considered the front-line therapies, have their limitations. Amphotericin B is expensive and requires cold-chain distribution and storage. The drug is administered intravenously but some Sudanese patients are unresponsive to it. Miltefosine is the only oral drug available but it is associated with teratogenicity and the potential of developing drug resistance is high. The situation presents a pressing need for safer and more effective anti-leishmanial treatments that are fit-for-purpose in poor countries.

Researchers in the School of Life Sciences at Dundee, working in collaboration with the Wellcome Trust Sanger Institute in Cambridge, have discovered a new protein that may hold the key to developing better, more effective nitro-drugs to tackle the disease. The findings are published in PLOS Pathogens.

The newly discovered protein, NTR2, is a nitroreductase found in leishmania parasites but absent in humans. NTR2 activates bicyclic nitro-compounds to form toxic products that kill the parasite. This discovery is useful for the development of novel treatments for visceral leishmaniasis.

Two classes of nitro-drugs were identified as curative in animal models of the visceral leishmaniasis. The most advanced is the unicyclic drug fexinidazole, which is currently being evaluated in phase II clinical trials in Africa. The second class consists of the bicyclic nitro-drugs, which are used to treat tuberculosis, including the recently approved drug delamanid. The bicyclic nitro-drugs have been reported as promising fast-track options for clinical trials in patients with visceral leishmaniasis. 

“One concern has been that if all nitro-drugs are activated by NTR1, then loss of this protein would lead to widespread drug resistance to both unicyclic drugs (fexinidazole) and bicyclic drugs (delamanid). We have discovered this new protein, NTR2 that specifically activates drugs like delamanid but not fexinidazole,” said Professor Alan Fairlamb, Wellcome Principal Research Fellow in the School of Life Sciences at Dundee, in a press statement. “This knowledge is extremely important in that it allows us to design better drugs activated by NTR2 and to suggest drug combinations that will reduce the risk of emergence of drug resistance through loss of either NTR1 or NTR2 activity. It also provides a potential diagnostic marker for resistance should it arise. Further work is now needed to find the most appropriate partner drugs to be used to increase efficacy and decrease toxicity in patients, to minimize the risk of drug resistance emerging and in designing second generation drugs.”

Source: University of Dundee