About Leishmania disease, lifecycle, diagnosis, current available medicines in market, potential drug targets(enzymes) with its mechanism of action.

2. INTODUCTION
EPIDEMIOLOGY & DIAGNOSIS
LIFECYCLE
ACCESS TO MEDICINE
POTENTIAL DRUG TARGET
REFERENCES

3. WHAT IS LEISHMANIASIS?
As per WHO;
• The leishmaniases are a group of diseases caused by protozoan parasites from more
than 20 Leishmania species
• These parasites are transmitted to humans by the bites of the infected female
phlebotomine sandfly - a tiny – only 2–3 mm long – insect vector. There are three main
forms of leishmaniasis: cutaneous, visceral or kala-azar, and mucocutaneous
• Most people infected by the parasite do not develop any symptom at all in their life.
Therefore, the term leishmaniasis refers to the fact of becoming sick due to
a Leishmania infection and not the mere fact of being infected with the parasite

4. EPIDEMIOLOGY
• Recurrent epidemics of visceral leishmaniasis in East Africa (Ethiopia, Kenya, South
Sudan and Sudan) have caused high morbidity and mortality in affected communities
• Almost 90% of mucocutaneous leishmaniasis cases occurs in the Plurinational State of
Bolivia, Brazil and Peru
• The disease is endemic in the tropical and subtropical regions of 88 countries. There
are an estimated 12 million cases worldwide; 1.5 to 2 million new cases occur every
year. Cutaneous forms are most common (1 to 1.5 million cases per year), representing
50 to 75% of all new cases, and 500,000 cases of VL occur every yea
DIAGNOSIS, DETECTION & SURVELLIANCE
• Demonstration and isolation of parasite
• DNA detection method
• Immunodiagnosis:
Antigen detection, Antibody detection, Skin testing

5. from: web.stanford.edu

6. CLASS DRUGS MOA
Antimonials Sodium Stiboluconate
(Pentostam)
By inhibition of –SH dependent enzyme
Diamidine Pentamidine
(Nebupent)
Interacts with kinetoplast DNA, inhibits topoisomerase
II, interfers with aerobic glycolysis
Antifungals Amphotericine B
(AmBisome)
Bind with ergosterol of cell membrane of parasites
forming micropores and leakage of cellular content
Ketoconazole Inhibiting conversion of lanosterol to ergosterol;
impairement of membrane function
Others Miltefosine (Impavido) Trigger programmed cell death
Paramomycine Action on ribosomes causing inhibition of protein
synthesis
Allopurinol Prototype of pyrazolopyrimidine; inhibit growth
ACCESS TO MEDICINES:

7. Na Stibogluconate
Pentamidine
Amphotericine B

8. POTENTIAL DRUG TARGETS:
NMT Inhibitor
Ornithine Decarboxylase
OSC Inhibitor
Protease
Protein Kinase & cytokinies
Pteridine Reductase

9. Spermidine Synthase
Sterol Methyl transferase
Succinate Dehydrogenase
Topoisomerase
Trypanothione Reductase

10. Enzyme MOA PDB
NMT inhibitor NMT catalyzes the transfer of myristate (a 14-carbon fatty
acid) to the N-terminal glycine of target proteins, either
cotranslationally or post-translationally
4CGL, 4CGP, 4CYN, 4CYO, 4CGN, 4CGO
Ornithine
Decarboxylase
Polyamine biosynthesis, essential for cell growth &
proliferation. Catalyzes conversion of L-ornithine to
putrescine (rate limiting step)
7ODC, 2ON3, ID7K, 1QU4
OSC Inhibitors Inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), an
enzyme in the cholesterol synthesis pathway, has the
unique ability to inhibit cholesterol synthesis while
simultaneously enhancing oxysterol synthesis
Trypanothione
Reductase
A flavoprotein oxidoreductase central to the unique thiol-
redox system that operates in trypanosomatid protozoa
4ADW, 2JK6, 1AOG, 2W0H
Topoisomerase Inhibit relaxation and decatenation reaction catalysed by
both type I & II
2B9S, 1A36, 1JUW
Glycerol 3
phosphate
Dehydrogenase
NAD-dependent glycerol-3-phosphate dehydrogenase
(GPDH) catalyzes the interconversion of dihydroxyacetone
phosphate and l-glycerol-3-phosphate
1EVY, 1EVZ, 1JDJ, 1N1E

11. Enzyme MOA PDB
Spermidine Synthase catalyzes the transfer of the propylamine group from S-
adenosylmethioninamine to putrescine in the biosynthesis of
spermidine, inhibiting spermidine reduces metabolic function
3RW9, 3B7P
Pteridine Reductase Pteridine reductase is a NADPH dependent short-chain
reductase(SDR) responsible for the salvage of pterins in the
protozoan Parasite Leishmania. This enzyme acts as a
metabolic bypass for drugs targeting Dihydrofolate reductase
1E7W, 2BFO, 1E92, 2BF7, 2QHX
Sterol
Methyltransferase
When flagellates exposed to azasterol complete growth and
cell lysis
Protein Kinase inhibits PKC activation and translocation to the membrane 1TVO, 402Z, 3PG1
Protease inhibitor 2XE4, 2KVK

12. Potential drug target of protein kinase
@ researchgate

13. Ornithine decarboxylase as potential drug target for leishmaniasis

14. REFERENCES:
• Jennie A Hutton, Victor Conclaves, Daniel Paape, Structure-Based Design of Potent and Selective
Leishmania N-Myristoyltransferase Inhibitors, Journal of Medicinal Chemistry, ACS Publication, 2014,
57, 8664−8670
• Rita Mukhopadhyay, R. Madhubala, Leislmania donovani: Cellular Control of Oru&hhe decarbxylase in
Promastigotes, Inr. J. Biochem. Cell Biol. Vol. 21,1995, No. 9, pp. 947-952
• Parth Das, Dibyendu Paik, Potential inhibitor in potential drug development for leishmaniasis, Int. J.
Biochemistry & Biophysics, vol 50, 2013, Pg No- 363-373
• Alicia Ponte-Sucre,Tanja Gulder, Structure-Activity Relationship and Studies on the Molecular
Mechanism of Leishmanicidal N,C-Coupled Arylisoquinolinium Salts, J. Med. Chem. 2009, 52, 626–636
• Jaspreet Kaur, Shyam Sundar, Molecular docking, structure–activity relationship and biological
evaluation of the anticancer drug monastrol as a pteridine reductase inhibitor in a clinical isolate of
Leishmania donovani, J Antimicrob Chemother 2010; 65: 1742–1748
• A. Kaiser,A. Gottwald, Targeting enzymes involved in spermidine metabolism of parasitic protozoa—a
possible new strategy for anti-parasitic treatment, Springer-Verlag 2003, Parasitol Res (2003) 91: 508–
516
• Juliany C. F. Rodrigues, amazonensis Promastigote and Amastigote Forms of -Sterol Methyltransferase
Inhibitor, on Induced by 22,26-Azasterol, a D24(25), ANTIMICROBIAL AGENTS AND
CHEMOTHERAPY,2002, p. 487–499

15. • Luis Carvalho, Juan Román Luque-Ortega, The 8 amino quinolone analogue Leishmania
donovani Promastigotes by Sitamaquine Causes Oxidative Stress in L.Donovani
targeting succinate dehydrogenase, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,
Sept. 2011, p. 4204–4210
• Benu Brata Das, Nilkantha Sen, Topoisomerase research of kinetoplastid parasite
Leishmania, with special reference to development of therapeutics, Review
article,Indian J Med Res 123, March 2006, pp. 221-232
• Ravi Kumar Gundampati , Medicherla V. Jagannadham, Molecular docking based
inhibition of Trypanothione reductase activity by Taxifolin novel target for
antileishmanial activity, Journal of Applied Pharmaceutical Science Vol. 2 (10), pp. 133-
136, October, 2012