Research Groups
Mammalian Biology: Malaria
Research Interests and Description
Staff Research Scientist: Dinkar Sahal, PhD
Group Leader: Virander Chauhan
Research Interests
Targeting malaria parasite with antimicrobial peptides, novel antimalarial drugs from Nature and via chemical synthesis.
Description of Research
Targeting malaria parasite with antimicrobial peptides
The ability of the malaria parasite to hoodwink both drugs and vaccines is a serious public health concern. It is clear that symbiotic association with bacteria has played a vital role in the evolution of the modern day malaria parasite. We have noted several bacterial features in the malaria parasite and the red blood cells it infects. These include the presence of apicoplast in the parasite, sensitivity of the parasite to antibiotics and externalization of the negatively charged phosphatidylserine from the inner to the outer leaflet in the infected red cell. Against this background, our studies with de novo designed antimicrobial peptides have inspired us to ask if these peptides can challenge the malaria parasite. Our results indicate that in comparison to the monomeric decapeptide ∆Fm {(Ac-GDFRKDFHKDFWA-NH2) (IC50> 100 micromolar)}, its tandemly repeated {(∆Fm)2, IC50 2.4 micromolar)} or lysine branched dimeric versions (∆Fd, IC50 1.39 micromolar) showed antimalarial potency two orders of magnitude greater. Rapid intracellular accumulation of FITC-∆Fd in red cell resident parasite, but not in the uninfected erythrocyte, showed selectivity for the malaria parasite. Overlaying DAPI (blue) and FITC (green) florescence suggested that ∆Fd binds with DNA. Trophozoite stage culture of malaria parasite incubated with ΔFd revealed that 95% of parasites were extracellular. In peptide treatment experiments, observation of intracellular parasite at shorter times and extracellular parasite at longer times suggests that ΔFd taken at IC50 to IC100 may trigger the process of parasite egress from inside the red cell. At these low dosesn when the action of the peptide is from inside the cell, ΔFd may be used to control malaria via premature egress. Alternatively, higher doses (5 times IC70), when ΔFd acts also from outside the infected cell, it may be used to cause selective lysis of parasitized cells suggesting a dual mode of action. The good therapeutic index of ΔFd, besides its ability to inhibit the growth of the chloroquine resistant Dd2 and INDO strains also, indicates the promise of this peptide against malaria.
Novel antimalarial drugs from nature and via chemical synthsesis
We are tapping into several different sources to provide potent, safe and affordable novel antimalarial drugs to the teeming millions who continue to be victimized by malaria. Our inputs include marine organisms and medicinal plants. Our strategy is SYBR Green fluorescence based on high throughput screening and short listing promising extracts, and high performance, chromatographic, bioactivity-guided purification of active molecules. These include one that inhibits the transition from Trophozoite to Schizont and another that blocks invasion by merozoites. We have embarked upon the path of structure determination of the most promising molecules using mass spectroscopic elemental analysis and fragmentation, NMR, UV and IR. Our aim is to pass from structure to chemical synthesis and comparative testing of natural vs synthetic molecules in a mouse model of malaria. In addition to molecules derived from nature, we are engaged in studying the potential of synthetically obtained chalcones, stilbenes, acridines and Indoles against malaria. Most recently, we have found that hybrids of chalcones and stilbenes target the malaria parasite in a stage-specific manner and kill the parasite by triggering parasite specific apoptosis.
Recent Publications
Bagavan, A., Rahuman, A.A., Kamaraj, C., Kaushik, N.K., Mohanakrishnan, D., Sahal, D. 2011. Antiplasmodial activity of botanical extracts against Plasmodium falciparum. Parasitol Res 108, 1099-1109 PubMed link
Dasgupta, S., Samantaray, S., Sahal, D., Rajendra, P. Roy, R.P. 2011. Isopeptide Ligation Catalyzed by Quintessential Sortase A: Mechanistic Cues from Cyclic and Branched Oligomers of Indolicidin. J Biol Chem 286, 23996-24006 PubMed link
Sharma, A., Sharma, N., Shard, A., Kumar, R., Mohanakrishnan, D., Saima, Sinha, A.K., Sahal, D. 2011. Tandem allylic oxidation–condensation/esterification catalyzed by silica gel: an expeditious approach towards antimalarial diaryldienones and enones from natural methoxylated phenylpropenes. Org Biomol Chem 14, 5211-5219 PubMed link
Anantharaman, A., Sahal, D. 2010. Reverse Engineering Truncations of an antimicrobial peptide dimer to identify the origins of potency and broad spectrum of action. J Med Chem 53, 6079-6088 PubMed link
Anantharaman, A., Sardar, M., Sahal, D. 2010. Synergy with rifampicin and kanamycin enhances potency, kill kinetics and selectivity of de novo designed antimicrobial peptides. Antimicrob Agents Chemother 54,1693-1699 PubMed link
Kumar, R., Mohanakrishnan, D., Sharma, A., Kaushik, N.K., Kalia, K., Sinha, A.K., Sahal, D. 2010. Reinvestigation of structure activity relationship of methoxylated chalcones as antimalarials: Green Synthesis and evaluation of 2,4,5-trimethoxy substituted patterns as lead candidates derived from abundantly available natural β-asarone. Eur J Med Chem 45, 5292-5301 PubMed link
