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Defence Health

Army Malaria Institute

Walter Reed Army Institute of Research (WRAIR) Laboratory (US Army Detachment)

Mission

To conduct research that supports the discovery of new antimalarial drugs for the treatment and protection of Australian and United States military personnel against malaria infections. In support of this mission the WRAIR Lab uses and develops tools ranging from molecular biology to clinical drug studies. The WRAIR Lab works closely with the Departments of Drug Resistance and Diagnostics (DRD) and Drug Evaluation (DE) in all studies.

Department Structure

Exchange officers from the Walter Reed Army Institute of Research (WRAIR) are part of the Engineer and Scientist Exchange Program (ESEP) between Australia and the United States. The WRAIR lab collaborates closely with DRD and DE Departments at AMI, as well as the Division of Experimental Therapeutics, WRAIR.

Current Research Projects

  1. Discovery of selective inhibitors of Pfmrk, a malarial protein kinase, as novel antimalarial agents. (Collaboration with WRAIR and University of Northern Colarado.)
  2. Discovery of selective inhibitors of malarial fatty acid biosynthesis enzymes. (Collaboration with WRAIR, John Hopkins University, Portland State University and University of Melbourne.)
  3. Develop new assay methods and analysis parameters to evaluate slow acting and stage specific antimalarials. (Collaboration with DE.)
  4. Investigate growth conditions of in vitro drug assays to better understand and correlate in vitro and in vivo efficacy data. (Collaboration with DE, WRAIR and John Hopkins University.)
  5. Study cell cycle control mechanisms within Plasomodium falciparum to identify and exploit novel drug targets. (Collaboration with WRAIR, DRD and DE.)
  6. Identify a role of protein kinases in artemisinin induced dormancy within Plasomodium falciparum. (Colaboration with DRD.)
  7. Discovery of natural products as potent antimalarial agents. (Collaboration with DE and University of Nairobi.)
  8. Assess malaria drug resistance within the South Pacific region. (Colaboration with DRD.)

Collaborators

Australian

  1. Queensland Institute of Medical Research (QIMR)
  2. University of Melbourne
  3. University of Queensland

International

  1. Division of Experimental Therapeutics, Walter Reed Army Institute of Research, USA.
  2. Malaria Research Institute, John Hopkins University
  3. University of Northern Colorado
  4. Portland State University
  5. World Health Organization
  6. University of Nairobi, Kenya
  7. United States Army Medical Research Unit - Kenya

Publications

2010

Halbert J, L Ayong, L Equinet, K Le Roch, M Hardy, D Goldring, L Reininger, NC Waters, D Chakrabarti, C Doerig. A Plasmodium falciparum transcriptional CDK-related kinase with a crucial role in parasite proliferation associates with histone deacetylase activity. Eukaryot Cell, 2010; 9(6):952-9.

Caridha D, AK Kathcart, D Jirage, NC Waters. Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases. Bioorg Med Chem Lett, 2010; (13):3863-7.

Jirage D, Y Chen, D Caridha, M O’Neil, F Eyase, W H Witola, CB Mamoun, NC Waters. The malarial CDK Pfmrk and its effector PfMAT1 phosphorylate DNA replication proteins and co-localize in the nucleus. Mol Biochem Parasit; 2010; 172(1):9-18.  

Jirage D, SM Keenan, NC Waters. Exploring novel targets for antimalarial drug discovery: plasmodial protein kinases. Infect Disord Drug Targets, 2010; 9(5). Epub ahead of print.

Kozlov S, NC Waters, M Chavchich. Leveraging cell cycle analysis in anticancer drug discovery to identify novel Plasmodial drug targets. Infect Disord Drug Targets, 2010; 9(5). Epub ahead of print.

Spalding MD, Eyase FL, Akala HM, Bedno SA, Prigge ST, Coldren RL, Moss WJ, Waters NC. Increased Prevalence of the pfdhfr/ pfdhps quintuple mutant and rapid emergence of pfdhps resistance mutations at codons 581 and 613 in Kisumu, Kenya. Malar J, 2010; 9: 338.

Waters NC. Promising drug targets in the identification of novel antimalarials. Infect Disord Drug Targets, 2010; 10 (3): 132-3.
2009

Co EM, RA Dennull, DD Reinbold, NC Waters, JD Johnson. Assessment of malaria in vitro drug combination screening and mixed-strain infections using the malaria Sybr green I-based fluorescence assay. Antimicrob Agents Chemother, 2009; 53(6):2557-63.

Yenesew A, H Twinomuhwezi, JM Kabaru, HM Akala, BT Kiremire, M  Heydenreich, MG Peter, FL Eyase, NC Waters, DS Walsh. Antiplasmodial and larvicidal flavonoids from Derris trifoliata. Bull. Chem Ethiop, 2009; 23(3):1-6. 

Geyer JA, SM Keenan, CL Woodard, PA Thompson, L Gerena, DA Nichols, CE Gutteridge, NC Waters. Selective inhibition of Pfmrk, a Plasmodium falciparum CDK, by antimalarial 1,3-diaryl-2-propenones. Bioorg Med Chem Lett, 2009.

Lois M Muiva,  A Yenesew, S Derese, M Heydenreich, MG Peter, HM Akala, NC Waters, C Mutai, JM Keriko, D Walsh. Antiplasmodial β-hydroxydihydrochalcone from seedpods of Tephrosia elata. Phytochemistry Letters, 2009.

Lee P J,  JB Bhonsle, H Gaona, J Johnson, TH Hudson, TN Heady, DP Huddler, M Kreishman-Deitrick, AK Bhattacharjee, L Gerena, N Roncal, M Lopez-Sanchez, ST Prigge, NC Waters. Targeting the fatty acid biosynthesis enzyme, PfKASIII, in the identification of novel antimalarial agents. J Med Chem, 2009; 52(4):952-63.

2008

Alhamadsheh MM, NC Waters, S Sachdeva, P Lee, KA Reynolds. Synthesis and biological evaluation of novel sulfonyl-naphthalene-1,4-diols as FabH inhibitors. Bioorg Med Chem Lett, 2008; 18(24):6402-5.

Doerig C, O Billker, T Haystead, P Sharma, A Tobin, NC Waters. Protein kinases of malaria parasites: an update. Trends Parasitol, 2008; 24(12):570-7.

2007

Woodard, C. L., S. M. Keenan; L. A. Gerena, W. J. Welsh, J. A. Geyer, N. C. Waters. 2007. Evaluation of broad spectrum protein kinase inhibitors to probe the architecture of the malarial cyclin dependent protein kinase Pfmrk. Bioorganic & Medicinal Chemistry Letters. 17: 4961-4966. 

Lanteri, C. A., J. D. Johnson, N. C. Waters. 2007. Recent Advances in Malaria Drug Discovery. Recent Patents Anti-Infective Drug Discovery. 2:95-114.

Johnson, J. D., R. A. Dennull, L. Gerena, M. Lopez-Sanchez, N. E. Roncal, N. C. Waters. 2007. Assessment and Continued Validation of the MSF Assay for Use in Malaria Drug Screening. Antimicrob Agents Chemother. 51(6):1926-1933.

2006

Alhamadsheh, M. M., N. C. Waters, D. P. Huddler, M. Kreishman-Deitrick, G. Florova, K. A. Reynolds. 2006. Synthesis and biological evaluation of thiazolidine-2-one 1,1-dioxide as inhibitors of Escherichia coli β-ketoacyl-ACP-synthase III (FabH). Bioorganic & Medicinal Chemistry Letters. 17(4):879-83.

Abosl, A. O., E. Mbukwa, B. H. Raserok, R. .R. Majinda, A. Yenesew, J. O. Midiwo, H. Akala, P. Liyala, N. C. Waters. 2006. Vangueria infausta root bark: in vivo and in vitro antiplasmodial activity.Br J Biomed Sci. 2006;63(3):129-33.

Chen, Y., D. Jirage, D. Caridha, A. K. Kathcart, E. Cortes, J. A. Geyer, S. T. Prigge, and N. C. Waters. 2006. Identification of an effector protein and gain-of-function mutants that activate Pfmrk, a malarial cyclin dependent protein kinase. Mol. Biochem. Parasit. 149:48-57.

Andayi, A.W., A. Yenesew,  S. Derese, J. O. Midiwo, P. M. Gitu, O. J. Jondiko, H. Akala, P. Liyala, J. Wangui, N. C. Waters, M. Heydenreich, and M. G. Peter. 2006. Antiplasmodial Flavonoids from Erythrina sacleuxii. Planta Med; 72(2):187-9.

21 September, 2011