About this Research Topic
Eradication of drug-resistant parasites will be a global challenge for the treatment of disabling, human protozoan diseases. Increasing number of re-emerging neglected tropical diseases in particular in Subsaharan Africa is alarming. During the last decade novel techniques have revolutionized the drug discovery process and should accelerate the identification of novel pathways and drug targets in these parasites. These methods comprise for example phenotypic screenings or the construction of DNA libraries.
The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers involved in fundamental processes i.e. cell proliferation, differentiation in particular developmental stages, and osmoregulation. Elucidation of cAMP regulated signaling pathways in parasites has just started in Plasmodium, a representative of the Apicomplexa phylum, and in Trypanosomatids causing important neglected tropical diseases. The present data show that these pathways are unique due to the absence of canonical G-proteins and G-protein coupled receptors (GPCR). Moreover, enzymes of the cyclic nucleotide signaling pathways in these parasites may substitute functionally the lack of canonical signaling proteins or differ in their structure compared to the human counterpart.
However, the uniqueness of cyclic nucleotide pathways in apicomplexan parasites and Kinetoplastids provides an opportunity to develop small molecules with a high selectivity. This has been shown recently for a cyclin-dependent-like kinase PfCLK3 which is essential for the parasite’s survival in the blood stages. The PFCLK3 was validated with the small molecule TDM 135-051 (4-(2-{3-[(Diethylamino)methyl]-2-methoxyphenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylbenzoic acid -tritrifluor-acetic acid) that exhibited multistage cross species parasiticidal activity without affecting the host orthologues. These results are encouraging with respect to foster the drug discovery process for novel compounds and targets.
Nevertheless, signals from the parasite trigger cAMP/CGMP regulated pathways in the human host cell during egress and invasion. In case of the Apicomplexan parasite T. gondii, the host immune response eliminates most of the parasites. Current knowledge suggests a strong interaction between immune regulated (IRG) host GTPases and parasite specific pseudokinases after invasion, implicating a novel strategy for pharmacological intervention.
This Research Topic welcomes Original Research, Review and Mini Review articles on novel, small molecules targeting enzymes of cAMP-regulated pathways in apicomplexan parasites and Kinetoplastids. The Research Topic also covers articles which focus on:
1. Screenings of novel targets in either apicomplexan parasites or Kinetoplastids
with possible drug candidates.
2. Optimization of small molecules which already inhibit canonical host enzymes to achieve better efficacy against the enzymes of the parasite.
3. Elucidation of molecular mechanisms of drug action in cAMP/CGMP regulated pathways in both groups of parasites.
4. Molecules or techniques which cause immunomodulation of host parasite interaction during cAMP/cGMP regulated invasion and egression.
The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers involved in fundamental processes i.e. cell proliferation, differentiation in particular developmental stages, and osmoregulation. Elucidation of cAMP regulated signaling pathways in parasites has just started in Plasmodium, a representative of the Apicomplexa phylum, and in Trypanosomatids causing important neglected tropical diseases. The present data show that these pathways are unique due to the absence of canonical G-proteins and G-protein coupled receptors (GPCR). Moreover, enzymes of the cyclic nucleotide signaling pathways in these parasites may substitute functionally the lack of canonical signaling proteins or differ in their structure compared to the human counterpart.
However, the uniqueness of cyclic nucleotide pathways in apicomplexan parasites and Kinetoplastids provides an opportunity to develop small molecules with a high selectivity. This has been shown recently for a cyclin-dependent-like kinase PfCLK3 which is essential for the parasite’s survival in the blood stages. The PFCLK3 was validated with the small molecule TDM 135-051 (4-(2-{3-[(Diethylamino)methyl]-2-methoxyphenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-isopropylbenzoic acid -tritrifluor-acetic acid) that exhibited multistage cross species parasiticidal activity without affecting the host orthologues. These results are encouraging with respect to foster the drug discovery process for novel compounds and targets.
Nevertheless, signals from the parasite trigger cAMP/CGMP regulated pathways in the human host cell during egress and invasion. In case of the Apicomplexan parasite T. gondii, the host immune response eliminates most of the parasites. Current knowledge suggests a strong interaction between immune regulated (IRG) host GTPases and parasite specific pseudokinases after invasion, implicating a novel strategy for pharmacological intervention.
This Research Topic welcomes Original Research, Review and Mini Review articles on novel, small molecules targeting enzymes of cAMP-regulated pathways in apicomplexan parasites and Kinetoplastids. The Research Topic also covers articles which focus on:
1. Screenings of novel targets in either apicomplexan parasites or Kinetoplastids
with possible drug candidates.
2. Optimization of small molecules which already inhibit canonical host enzymes to achieve better efficacy against the enzymes of the parasite.
3. Elucidation of molecular mechanisms of drug action in cAMP/CGMP regulated pathways in both groups of parasites.
4. Molecules or techniques which cause immunomodulation of host parasite interaction during cAMP/cGMP regulated invasion and egression.
Keywords: cAMP, cGMP, Parasites, Drug Resistance
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