Activity of a trisubstituted pyrrole in inhibiting sporozoite invasion and blocking malaria infection.

Antimicrobial Agents and Chemotherapy
Dhruv Panchal, Purnima Bhanot

Abstract

Malaria infection is initiated by Plasmodium sporozoites infecting the liver. Preventing sporozoite infection would block the obligatory first step of the infection and perhaps reduce disease severity. In addition, such an approach would decrease Plasmodium vivax hypnozoite formation and therefore disease relapses. Here we describe the activity of a trisubstituted pyrrole, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl] pyridine, in inhibiting motility, invasion, and consequently infection by P. berghei sporozoites. In tissue culture, the compound was effective within the first 3 h of sporozoite addition to HepG2 cells. In vivo, intraperitoneal administration of the compound significantly inhibited liver-stage parasitemia in P. yoelii sporozoite-infected mice and prevented the appearance of blood-stage parasites. P. berghei sporozoites lacking the parasite cGMP-dependent protein kinase, the primary target of the compound in erythrocyte-stage parasites, remained infectious to HepG2 cells and sensitive to the drug. These results suggest that the drug has an additional target(s) in sporozoites. We propose that drugs that inhibit sporozoite infection offer a feasible approach to malaria prophylaxis.

References

Mar 1, 1991·Transactions of the Royal Society of Tropical Medicine and Hygiene·T PonnuduraiJ H Meuwissen
Sep 13, 1988·Journal of Immunological Methods·L RéniaD Mazier
Mar 1, 1985·Molecular and Biochemical Parasitology·A L Schwartz, M R Hollingdale
Oct 1, 1981·The Journal of Experimental Medicine·N YoshidaR S Nussenzweig
Oct 3, 1998·Antimicrobial Agents and Chemotherapy·S M GanttP Sinnis
Jun 24, 2005·Infection and Immunity·Darcy L Medica, Photini Sinnis
Dec 6, 2005·Molecular and Biochemical Parasitology·Carmen A DiazPaul A Liberator
Apr 28, 2006·Antimicrobial Agents and Chemotherapy·Alida CoppiPhotini Sinnis
Dec 30, 2006·PLoS Medicine·Maëlle CarrazDominique Mazier
Jan 24, 2008·Antimicrobial Agents and Chemotherapy·Nassira MahmoudiDominique Mazier
Sep 26, 2009·PLoS Pathogens·Robert W MoonOliver Billker
Oct 31, 2009·Nature Reviews. Drug Discovery·Dominique MazierGeorges Snounou
Nov 27, 2009·The Journal of Biological Chemistry·Adebola FalaePurnima Bhanot

❮ Previous
Next ❯

Citations

Nov 30, 2011·Journal of Medicinal Chemistry·Tiago RodriguesFrancisca Lopes
Nov 7, 2012·Antimicrobial Agents and Chemotherapy·Alexis N LacrueDennis E Kyle
Dec 15, 2015·The Journal of Infectious Diseases·A Castellanos-GonzalezA C White
Feb 12, 2013·Bioorganic & Medicinal Chemistry Letters·Tyrell TowlePurnima Bhanot
Mar 19, 2016·Bioorganic & Medicinal Chemistry Letters·Rita C C CarvalhoNúbia Boechat
Dec 24, 2010·Cellular Microbiology·David A Baker
May 23, 2012·Microbes and Infection·Christine S HoppDavid A Baker
Jan 13, 2011·FEMS Microbiology Reviews·Matthew K Gould, Harry P de Koning
Jan 1, 2013·Experimental Parasitology·Audrey O T LauPurnima Bhanot
Nov 29, 2016·Nature Reviews. Microbiology·Mariana De NizVolker T Heussler
Feb 23, 2021·Frontiers in Microbiology·David RotellaPurnima Bhanot
May 18, 2018·Journal of Medicinal Chemistry·Diego González CabreraKelly Chibale

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Babesiosis

Babesiosis is caused by parasites of the genus babesia, which are transmitted in nature by the bite of an infected tick. Discover the latest research on babesiosis here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.