An Antiparasitic Compound from the Medicines for Malaria Venture Pathogen Box Promotes Leishmania Tubulin Polymerization.

ACS Infectious Diseases
Imran UllahDawn M Wetzel

Abstract

The few frontline antileishmanial drugs are poorly effective and toxic. To search for new drugs for this neglected tropical disease, we tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Screening yielded six discovery antileishmanial compounds with EC50 values from 50 to 480 nM. Concentration-response assays demonstrated that the best hit, MMV676477, had mid-nanomolar cytocidal potency against intracellular Leishmania amastigotes, Trypanosoma brucei, and Plasmodium falciparum, suggesting broad antiparasitic activity. We explored structure-activity relationships (SAR) within a small group of MMV676477 analogs and observed a wide potency range (20-5000 nM) against axenic Leishmania amastigotes. Compared to MMV676477, our most potent analog, SW41, had ∼5-fold improved antileishmanial potency. Multiple lines of evidence suggest that MMV676477 selectively disrupts Leishmania tubulin dynamics. Morphological studies indicated that MMV676477 and analogs affected L. amazonensis during cell division. Differential centrifugation showed that MMV676477 promoted partitioning of cellular tubulin toward the polymeric form in parasites. Turbidity assays ...Continue Reading

References

Dec 1, 1992·The Journal of Antimicrobial Chemotherapy·S L CroftA W Randall
Dec 1, 1996·Molecular Biology and Evolution·P J Keeling, W F Doolittle
Jan 1, 1997·Reviews of Environmental Contamination and Toxicology·R GroverH B Schiefer
Jun 17, 1998·Nature Structural Biology·E NogalesJ Löwe
Feb 24, 1999·Molecular and Biochemical Parasitology·K A WerbovetzD L Sackett
Feb 13, 2001·Current Opinion in Cell Biology·S K Dutcher
Nov 13, 2001·Tropical Medicine & International Health : TM & IH·S Sundar
Aug 6, 2002·Bioorganic & Medicinal Chemistry Letters·Gautam BhattacharyaKarl A Werbovetz
Sep 12, 2002·Expert Opinion on Therapeutic Targets·Karl A Werbovetz
Oct 9, 2002·Mini Reviews in Medicinal Chemistry·Karl A Werbovetz
Feb 18, 2003·Molecular Biology of the Cell·D M WetzelL D Sibley
Oct 11, 2003·Molecular and Biochemical Parasitology·Sophie GoyardStephen M Beverley
Apr 24, 2004·Antimicrobial Agents and Chemotherapy·Martin SmilksteinMichael Riscoe
Nov 10, 2004·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Marc OuelletteBarbara Papadopoulou
Jan 19, 2006·Clinical Microbiology Reviews·Simon L CroftAlan H Fairlamb
Dec 28, 2006·Nature Protocols·Brian Y Feng, Brian K Shoichet
Jun 27, 2008·Proceedings of the National Academy of Sciences of the United States of America·David PlouffeElizabeth A Winzeler
Dec 19, 2008·Chemical Biology & Drug Design·Rachel E MorganKarl A Werbovetz
Feb 11, 2010·Antimicrobial Agents and Chemotherapy·Christopher MaNaomi Morrissette
May 21, 2010·Nature·Francisco-Javier GamoJose F Garcia-Bustos
May 21, 2010·Nature·W Armand GuiguemdeR Kiplin Guy
Apr 8, 2011·Molecular and Biochemical Parasitology·Michelle F PaguioPaul D Roepe
Sep 20, 2011·Eukaryotic Cell·Audrey AmbitJeremy C Mottram
Jan 12, 2013·ChemMedChem·Lluís BallellNicholas Cammack
Feb 27, 2013·Memórias do Instituto Oswaldo Cruz·Francehuli DaggerCarlos Ayesta
Oct 6, 2015·Nature Reviews. Drug Discovery·Kei KatsunoB T Slingsby
Feb 2, 2016·Nature Chemical Biology·Panayotis C TheodoropoulosDeepak Nijhawan
Jun 15, 2016·Antimicrobial Agents and Chemotherapy·Diana OrtizScott M Landfear
Jun 16, 2016·Frontiers in Immunology·Anne GeigerPhilippe Holzmuller
Dec 13, 2016·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Naomi AronsonAlan Magill

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Related Concepts

Related Feeds

African Trypanosomiasis

African trypanosomiasis, also known as sleeping sickness, is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei and almost invariably progresses to death unless treated. Discover the latest research on African trypanosomiasis here.

Antiparasitics

Antiparasitics are medications which are indicated for the treatment of parasitic diseases. Discover the latest research on antiparasitics here.