Perspective on current and emerging drugs in the treatment of acute and chronic toxoplasmosis

Postgrad Med. 2019 Nov;131(8):589-596. doi: 10.1080/00325481.2019.1655258. Epub 2019 Aug 26.

Abstract

No new drugs for treatment of toxoplasmosis have been approved in over 60 years, despite the burden of toxoplasmosis on human society. The small selection of effective drugs is limited by important side effects, often limiting patient use. This perspective highlights promising late-stage drug candidates in the treatment of toxoplasmosis. Presently, drugs target the tachyzoite form of the parasite Toxoplasma gondii responsible for the acute infection but do not eradicate the tissue cyst form underlying chronic infection. Pyrimethamine - the first-line and only approved drug for treatment of toxoplasmosis in the United States - inhibits parasite DNA synthesis by inhibiting dihydrofolate reductase (DHFR). Two novel DHFR inhibitors with improved potency and selectivity for parasite DHFR over human DHFR are in clinical-stage development. One of the most advanced and promising therapeutic targets, demonstrating potential to treat both acute and chronic toxoplasmosis, is the calcium-dependent protein kinase 1 (CDPK1) which plays an essential role in the intracellular replicative cycle of the parasite, and has no direct mammalian homolog. Two CDPK1 inhibitor programs have identified potent and selective lead series, demonstrating acceptable systemic and CNS exposure, and in vivo efficacy in animal models of acute and chronic infection. Physicians need a better arsenal of parasiticidal drugs for the treatment of toxoplasmosis, particularly those active against tissue cysts.

Keywords: CDPK1; DHFR; Toxoplasmosis; calcium-dependent protein kinase 1; dihydrofolate reductase; pyrimethamine.

Publication types

  • Review

MeSH terms

  • Acute Disease
  • Animals
  • Antiprotozoal Agents / adverse effects
  • Antiprotozoal Agents / pharmacology
  • Antiprotozoal Agents / therapeutic use*
  • Calcium-Binding Proteins / antagonists & inhibitors*
  • Chronic Disease
  • Folic Acid Antagonists / adverse effects
  • Folic Acid Antagonists / pharmacology
  • Folic Acid Antagonists / therapeutic use*
  • Humans
  • Protein Kinases
  • Protozoan Proteins / antagonists & inhibitors*
  • Pyrimethamine / therapeutic use
  • Tetrahydrofolate Dehydrogenase
  • Toxoplasma
  • Toxoplasmosis / drug therapy*
  • United States

Substances

  • Antiprotozoal Agents
  • CDPK2 protein, Toxoplasma gondii
  • Calcium-Binding Proteins
  • Folic Acid Antagonists
  • Protozoan Proteins
  • Tetrahydrofolate Dehydrogenase
  • Protein Kinases
  • Pyrimethamine