Erythrocyte G protein as a novel target for malarial chemotherapy

PLoS Med. 2006 Dec;3(12):e528. doi: 10.1371/journal.pmed.0030528.

Abstract

Background: Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum.

Methods and findings: We investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target. Erythrocyte "ghosts" loaded with a Gs peptide designed to block Gs interaction with its receptors, were blocked in beta-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte Gs is functional and that propranolol, an antagonist of G protein-coupled beta-adrenergic receptors, dampens Gs activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host Gs to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other beta2-antagonists. beta-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection.

Conclusions: Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Antiprotozoal Agents / therapeutic use
  • Artemisinins / therapeutic use
  • Drug Therapy, Combination
  • Erythrocyte Membrane / chemistry
  • Erythrocyte Membrane / drug effects
  • Erythrocyte Membrane / parasitology
  • Erythrocyte Membrane / physiology
  • Erythrocytes / chemistry
  • Erythrocytes / drug effects*
  • Erythrocytes / parasitology
  • Erythrocytes / physiology*
  • GTP-Binding Proteins / drug effects*
  • Humans
  • Malaria / drug therapy
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Nucleotidases / analysis
  • Plasmodium falciparum / drug effects
  • Propranolol / pharmacology*
  • Propranolol / therapeutic use
  • Sesquiterpenes / therapeutic use
  • Signal Transduction / physiology
  • Trophozoites / drug effects

Substances

  • Adrenergic beta-Antagonists
  • Antimalarials
  • Antiprotozoal Agents
  • Artemisinins
  • Sesquiterpenes
  • artemisinin
  • Propranolol
  • Nucleotidases
  • adenosine monophosphatase
  • GTP-Binding Proteins

Associated data

  • SWISSPROT/P07550
  • SWISSPROT/P29992
  • SWISSPROT/P63092
  • SWISSPROT/P63096
  • SWISSPROT/P90582