Biology Reference
In-Depth Information
restricted to cases refractory to melarsoprol because of its high cost and lengthy
administration regime (Delespaux and De Koning
2007
).
The two treatments for acute American trypanosomiasis are nifurtimox and
benznidazole, neither of which is particularly effective against chronic disease
(Urbina
2010
). Although taken orally, the lengthy treatment course of 30-60 days
together with dose and time-related side effects (e.g., anorexia, weight loss, nausea
and vomiting, skin rashes, and neuropathy) contributes to a high rate of noncom-
pliance (Castro et al.
2006
).
First-line therapies for the leishmaniases (CL and VL) are the pentavalent
antimonies (Croft and Coombs
2003
), except in India where these drugs are
ineffective against VL due to the emergence of drug-resistant strains (Olliaro et al.
2005
). In such cases, three drugs are available: lipid formulations of amphotericin B
(high cost can be restrictive), paromomycin (more side effects than amphotericin B),
and miltefosine (contraindicated in pregnancy due to its teratogenicity) (Olliaro et al.
2005
).
There are currently no new drugs in clinical development for Chagas disease
or leishmaniasis. Two clinical trials have recently been conducted for HAT, one
for an orally available derivative of pentamidine (DB289) and the other for a
nifurtimox-eflornithine combination therapy (NECT): the development of DB289
has now been halted due to late renal toxicity (Paine et al.
2010
), but NECT
appears to offer some improvement on the standard eflornithine monotherapy
(Priotto et al.
2009
).
1.3 Cyclic Nucleotide Signaling in the Kinetoplastid Parasites
A role for cAMP signaling in the cell biology and virulence of kinetoplastids was
first suggested by Strickler and Patton (Strickler and Patton
1975
) for the rodent
trypanosome
T. lewisi,
by Mancini and Patton (Mancini and Patton
1981
) for
T. brucei
, and by Walter et al. (Walter et al.
1978
) for
L. donovani
. However,
progress in this area has been slow and more than 30 years later many of the
fundamental questions remain unanswered (Seebeck et al.
2004
; Kunz et al.
2009b
).
A major impediment was the implicit assumption by many researchers that cAMP
signaling in kinetoplastids was organized according to the accepted paradigms in
higher organisms at that time, most notably mammals. As a consequence, many
experiments were designed and results interpreted with the mammalian models in
mind, only to be followed by the slow realization that most of what seemed to be
“highly conserved” components of eukaryotic cAMP signaling networks were not,
in fact, conserved in the kinetoplastids.
For example, kinetoplastid class II adenylate cyclases (AC) are structurally
distinct from mammalian class I ACs. Mammalian ACs contain several transmem-
brane domains and are regulated by G-protein-coupled receptors. Kinetoplastid
ACs contain a single transmembrane region, flanked on one side by an extracellular
