Faculty Profile

Areas of Research: Malaria parasite membrane transport physiology; mechanisms of purine and drug transport; development of novel antimalarial drugs that target the primary malaria purine import transporter

Professional Interests

Malaria Parasite Physiology and Mechanisms of Nucleoside and Drug Transport

Malaria is a major public health problem affecting large areas of the world. About 600,000 people, mostly children and pregnant woman, die each year due to malaria. Malaria is caused by unicellular parasites from the Plasmodium species that grow inside erythrocytes. Plasmodium falciparum causes the most lethal form of malaria. Plasmodium spp. parasites are purine auxotrophs and require an exogenous source of purines to survive. They import purine precursors from the host erythrocyte via equilibrative nucleoside transporters (ENTs). Knockout of PfENT1 is lethal at purine concentrations found in human plasma. This suggests that PfENT1 inhibitors might kill parasites and represent a novel target for antimalarial drug development. We seek to characterize the purine nucleoside transporters and identify inhibitors as potential antimalarial drugs.

We have developed a yeast-based high throughput screen to identify PfENT1 inhibitors. We screened a 65,000 compound library and identified 171 hits. The nine best hits block PfENT1 and kill P. falciparum parasites in culture. We are characterizing the hits and exploring the SAR for the compounds to identify more potent derivatives. Additional work is focused on testing the hits against P. vivax ENT1 and in a mouse malaria model. In addition, in collaboration with GSK, they used our assay to screen their 1.8 million compound library. They have given us six of the best hits to develop as novel antimalarial drugs. We are currently in the hit-to-lead medicinal chemistry process to improve the potency and physicochemical properties of the hits. We are also investigating the molecular basis of their interaction with PfENT1 and the mechanism of their parasitocidal activity.

For additional information see Einstein News Release: Einstein Scientists Develop Novel Technique for Finding Drugs to Combat Malaria


Selected Publications

  1. Brass, L.F., Akabas, M.H., Burnley, L.D., Engman, D.M., Wiley, C.A., Andersen, O.S. (2010) An analysis of career choices made by graduates of 24 MD-PhD programs. Acad. Med. 85:692-701.
  2. Frame, I.J.*, Deniskin, R.*, Arora, A., and Akabas, M.H. (2015) Purine Import into Malaria Parasites as a Target for Antimalarial Drug Development. Ann. NY Acad. Sci. 1342:19-28 (*contributed equally)
  3. Frame, I.J.*, Deniskin, R.*, Rinderspacher, A., Katz, F., Deng, S-X., Moir, R.D., Adjalley, S.H., Coburn-Flynn, O, Fidock, D.A., Willis, I.M., Landry, D.W., and Akabas, M.H. (2015) Yeast-based High-Throughput Screen Identifies Plasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitors That Kill Malaria Parasites. ACS Chem. Biol. 10(3):775-83. (*contributed equally)
  4. Akabas MH. Cysteine Modification: Probing Channel Structure, Function and Conformational Change. In: Novel Chemical Tools to Study Ion Channel Biology (Eds. Ahern, C. and Pless, S.) Springer Int. Publishing.  Adv Exp Med Biol. 2015; 869:25-54.
  5. Deniskin R, Frame IJ, Sosa Y, Akabas MH. Targeting the Plasmodium vivax Equilibrative Nucleoside Transporter 1 (PvENT1) for antimalarial drug development. (2016) Int. J. Parasitol. Drugs & Drug Resistance. 6:1-11.
  6. Arora A, Deniskin R, Sosa Y, Nishtala SN, Kumar TRS, Henrich PP, Fidock DA, Akabas MH. (2016) Substrate and inhibitor specificity of the Plasmodium berghei Equilibrative Nucleoside Transporter Type 1 (PbENT1). Mol Pharmacol. 89(6):678-85.
  7. Nishtala SN*, Arora A*, Reyes J, Akabas MH. (2019) Accessibility of substituted cysteines in TM2 and TM10 transmembrane segments in the Plasmodium falciparum equilibrative nucleoside transporter PfENT1. J Biol Chem. 294:1924-1935. PubMed PMID: 30541922. (*contributed equally)
  8. Sosa Y*, Deniskin R*, Frame IJ*, Steiginga MS, Bandyopadhyay D, Graybill TL, Kallal LA, Ouellette MT, Pope AJ, Widdowson KL, Young RJ, Akabas MH. Parallel Hit Progression Strategy Identifies Improved Small Molecule Inhibitors of the Malaria Purine Uptake Transporter that Inhibit Plasmodium falciparum Parasite Proliferation. ACS Infectious Dis. 2019; 5:1738−1753. (*contributed equally)
  9. Brass LF, Akabas MH. The national MD/PhD program outcomes study: 1. Training and career paths of program graduates. JCI Insight 2019; 4(19):e133009. https://doi.org/10.1172/jci.insight.133009
  10. Akabas MH, Brass LF. The national MD/PhD program outcomes study: 2. Outcomes variation by gender, race and ethnicity. JCI Insight 2019; 4(19):e133010. https://doi.org/10.1172/jci.insight.133010

Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Ullmann Building, Room 209
Bronx, NY 10461

Tel: 718.430.3360
Fax: 718.430.8819

Research Information