Fighting Leishmania with Synthetic Glycoside 

When sandflies infected with the Leishmania parasite bite us, the motile form with flagellum, the promastigote, enters the host. Under the skin, our macrophages find and engulf them. During phagocytosis, the parasite discards its flagellum and becomes amastigote. 

Leishmania promastigote and amastigote. Images by Stefan Walkowsky via Wikimedia Commons

To facilitate entry and ensure survival in the macrophage, there is leishmanolysin, a glycoprotein, on the surface of the Leishmania parasite. If we can interfere with this glycoprotein, the parasite will fail to enter and survive inside the macrophages; other immune components will eliminate the extracellular form. 

Lalit Garg and team at the NII had come across studies reporting the antimalarial and anti-parasitic effects of plant-derived glycosides. So they thought of designing glycosides that could interfere with the function of leishmanolysin. To test the idea, they collaborated with scientists at other institutions.

By modifying the structure of glucose, Ram Sagar from JNU and Chintam Narayana from the Shiv Nadar University designed and synthesised twelve different glycosides. 

While Nishant Joshi from Shiv Nadar University checked the docking of these glycosides with leishmanolysin using molecular simulations, Amrita Chakrabarti started testing these glycosides for antileishmanial activity in vitro on Leishmania parasite cultures. 

Using in silico studies, Nishant identified the glycoside that is most effective in binding to leishmanolysin. Amrita found that the same glycoside was highly effective in killing the parasites even at low concentrations.

But how does the glycoside work?

The researchers examined the reactive oxygen species levels inside the parasite. The glycoside increased intracellular reactive oxygen species levels. Measuring the membrane potential of the parasite, the team found that the glycoside caused depolarisation of the membranes. These, together, effectively killed the parasites.

Is the glycoside toxic to mammalian hosts, wondered the researchers. 

They used canine kidney cells to test. The glycoside was not toxic.  

The present treatment of leishmaniasis uses toxic antimony compounds and antifungals with limited benefits. So the glycoside formulation may be a boon for patients with leishmaniasis. But, of course, before using the new glycoside for treating patients, further in vivo studies and clinical trials are needed.

Frontiers in Cellular and Infection Microbiology, 2022;
DOI: 10.3389/fcimb.2022.803048

Reported by Tanya Jain
Chemical Glycobiology Lab, National Institute of Immunology, New Delhi

*This report was written in a workshop on science writing organised by NII, New Delhi

Tagged as: Banaras Hindu University, glycoside, leishmanolysin, Metalloprotease Gp63, National Institute of Immunology, Shiv Nadar University

Categorised in: Delhi, Therapeutics, Uttar Pradesh