Targeting Folate Metabolism: A Promising Therapeutic Rationale against Brugia malayi Infection

• Published in: Indian journal of clinical biochemistry Vol. 30; no. S1; p. S25
• Main Authors: Bhoj, Priyanka, Hande, Sneha, Wagh, Suraj, Sharma, Richa, Goswami, Kalyan, Jena, Lingaraj, Reddy, Maryada Venkata Rami
• Format: Journal Article
• Language: English
• Published: Springer 24-05-2022
• Subjects: Biological products; Dihydrofolate reductase; Folic acid; Health aspects; Physiological aspects
• ISSN: 0970-1915

Lymphatic filariasis although not fatal, is a profoundly disabling disease, with an estimated level of 5.8 million disability adjusted life year. Besides being almost sole drug, DEC have various limitations. Hence exploration of effective filarial target is now needful. Taking clue from earlier promising results with certain plant extracts having polyphenolic ingredients as well as synthetic compounds with potential DHFR inhibitory effect, we postulated a plausible link between folates and polyphenolics based on their common precursor in shikimate metabolism. With the perspective of structural similarity based antagonism, we have attempted to validate parasitic dihydrofolate reductase (DHFR) enzyme and associated folate metabolism for therapeutic target. For this purpose, initial bioinformatics approach for molecular docking and further validation by in vitro assay using green tea extract as a probe followed by folate reversal study and synergistic effect with piperidine compound. A comparative docking analysis between human and Brugia malayi DHFR showed remarkably effective binding parameters with lower inhibition constants of these ligands with parasitic target, but not with human counterpart suggesting safety and efficacy. The virtual results were further validated by significant in vitro antiparasitic effect of green tea extract followed by folate reversal assay and marked synergistic impact with piperidine compound confirming the involvement of folate pathway. Finally, we recorded the anti-folate induced apoptosis indicating impairment in DNA synthesis due to DHFR inhibition. Therefore, we conclude that DHFR might be considered as a valid target for drug design with reasonable safety and efficacy.