Biology Reference
In-Depth Information
challenges. A fundamental issue relevant to all three genera involves the identification
of selective inhibitors that target the essential PDEs. Ideally, cross-reactivity with the
various human PDE families should be minimal. The feasibility of finding a solution
to this challenge can be judged by comparison with the successful development of
selective inhibitors for the human PDEs. The identification of drugs specific for human
PDE3, PDE4, and PDE5 illustrates that genetic differences between PDE families can
be sufficient to enable the development of selective inhibitors (Bender and Beavo
2006
). Bearing in mind the urgent need for new therapies and the desirability of a
relatively short duration of treatment, the requirement for very stringent selectivity
might be relaxed somewhat if the drug was efficacious and its side effects were
acceptable and reduced compared to current treatments.
Another important consideration is minimization of the development of drug
resistance. This has been best studied in
T. brucei
, where mutations in the P2 purine
transporter, TbAT1, and the high-affinity pentamidine transporter, HAPT1, result in
decreased importation of melarsoprol and pentamidine into the cell, reducing
their trypanocidal efficacy (De Koning
2008
). Melarsoprol resistance has also
been demonstrated in laboratory strains overexpressing the multidrug resistance-
associated protein, TbMRPA, which showed increased export of drugs from the cell
(Luscher et al.
2006
). A preliminary assessment of candidate drug interactions with
these transporters, especially PDE inhibitors with purine-like scaffolds, may help
circumvent these common resistance mechanisms. Resistance is less likely to
occur with compounds that enter the cell by more than one route, e.g., a combina-
tion of active and passive transport or via multiple active transport mechanisms
(transporter- or receptor-mediated). Lack of interaction with TbAT1, HAPT1, and
TbMRPA would also avoid problems of cross-resistance.
One of the main disease-specific challenges that must be met in order for a PDE
inhibitor to progress from a hit to lead compound is its ability to gain access to the
parasite within the host. In the case of
T. brucei
, it is essential that the compound be able
to cross the blood-brain barrier for it to be effective against late-stage CNS disease. For
T. cruzi
and
Leishmania
which, unlike
T. brucei
, are intracellular parasites, the com-
pound must not only be able to cross the host cell membrane, but also the parasite
membrane in sufficiently high concentrations, and at a sufficient rate, to kill the parasite.
Additionally, any potential therapy for neglected diseases must take into consider-
ation the inability of the patient to pay for treatment and the lack of adequate hospital
facilities. Ideally, compounds should be cheap to produce, stable in the environments
where they will be used, have a short treatment course, and be easy to administer
(preferably oral) to ensure patient compliance and to diminish the risk of resistance.
4 Perspective
Although past progress has been slow, more recently, significant strides have been
made in our understanding of the importance of cAMP signaling in kinetoplastid
function. These findings provide genetic and pharmacological validation of the
