Biomedical Engineering Reference
In-Depth Information
and not the other). Such reagents will help identify the relative ecacy (in terms
of killing parasites) of inhibiting each enzyme alone and in combination as well
as allow a greater understanding of how malaria parasites acquire nutrients
from inside and outside the erythrocyte. Together, such biological insights will
be imperative for driving the overall drug-development strategy for this enzyme
system towards either a conventional approach that targets one or the other
enzyme or a single molecule (or combination therapy) that inhibits both PfA-
M1 and PfA-M17. The latter strategy in particular may reduce the likelihood of
parasites being able to evolve rapid resistance.
7.4 Conclusions
Agents that inhibit the aminopeptidase enzymatic activity in parasites have
been shown to control both laboratory and murine models of malaria. Simi-
larly, both PfA-M1 and PfA-M17 are highly conserved among all Plasmodium
species, thus indicating that future therapeutics could deliver cross-species
inhibition and validate the use of rodent models of malaria (e.g. P. c. chabaudi
and P. berghei) in the search for novel drugs targeting these enzymes.
Acknowledgments
DLG is an NHMRC Career Development Award recipient. JPD is a CIHR
Canada Research Chair (Tier 1) in Infectious Diseases. SM is an ARC Future
Fellow. We thank the NHMRC (Grant Number 571917) and the ARC for
funding support. We thank the Australian synchrotron for beamtime and for
technical assistance.
References
1. P. D. Crompton, S. K. Pierce and L. H. Miller, J. Clin. Invest., 2010, 120,
4168-4178.
2. U. D'Alessandro, Expert Opin. Pharmacother., 2009, 10, 1291-1306.
3. R. Chilengi and J. Gitaka, Malar. J., 2010, 9 (Suppl 3), S1.
4. World Health Organization, World Malaria Report, World Health Orga-
nization, Switzerland, 2009.
5. M. Enserink, Science, 2010, 328, 844-846.
6. D. L. Gardiner, T. S. Skinner-Adams, C. L. Brown, K. T. Andrews, C. M.
Stack, J. S. McCarthy, J. P. Dalton and K. R. Trenholme, Expert Rev. Anti
Infect. Ther., 2009, 7, 1087-1098.
7. T. S. Skinner-Adams, C. M. Stack, K. R. Trenholme, C. L. Brown, J.
Grembecka, J. Lowther, A. Mucha, M. Drag, P. Kafarski, S. McGowan, J.
C. Whisstock, D. L. Gardiner and J. P. Dalton, Trends Biochem. Sci., 2010,
35, 53-61.
8. T. Burki, The Lancet, 2009, 9, 213.
9. T. N. C. Wells, P. L. Alonso and W. E. Gutteridge, Nat. Rev. Drug Discov.,
2009, 8, 879-891.
