The online version of this article (doi:10.1186/1475-2875-11-54) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
RM: Performed all the experiments and analyzed the data. ZDX: Synthesized 17-AAG and 17-PEG-Alkyn-GA. AKHW: Characterized the structure of 17-PEG-Alkyn-GA by NMR. VJD: Conceived the idea of synthesizing 17-PEG-Alkyn-GA, helped in drafting the manuscript. GKJ: Conceived the study, planned the experiments, interpreted the results and wrote manuscript. All authors read and approved the final manuscript.
Geldanamycin (GA), a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodyamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the cured animals to malaria reflected in an attenuated parasite load that may be evoked by a protective immune response in the host.
Six weeks old Swiss mice were infected with a lethal Plasmodium yoelii (17XL) strain. On appearance of clinical symptoms of malaria, these animals were treated with two different GA derivatives and the parasite load was monitored over 15-16 days. Drug-treated animals cured of the parasite were then re-challenged with a lethal dose of P. yoelii 17XL. Serum samples from GA cured mice that were re-challenged with P. yoelii 17XL were examined for the presence of antibodies against the parasite proteins using western blot analysis.
Treatment of P. yoelii 17XL infected mice with GA derivatives showed slow recovery from clinical symptoms of the disease. Blood smears from drug treated mice indicated a dominance of ring stage parasites when compared to controls. Although, P. yoelii preferentially invades normocytes (mature rbcs), in drug-treated animals there was an increased invasion of reticulocytes. Cured animals exhibited robust protection against subsequent infection and serum samples from these animals showed antibodies against a vast majority of parasite proteins.
Treatment with GA derivatives blocked the transition from ring to trophozoite stage presumably by the inhibition of HSP90 associated functions. Persistence of parasite in ring stage leads to robust humoral immune response as well as a shift in invasion specificity from normocytes to reticulocyte. It is likely that the treatment with the water-soluble GA derivative creates an attenuated state (less virulent with altered invasion specificity) that persists in the host system, allowing it to mount a robust immune response.
Additional file 1: Structural characterization of 17-PEG-Alkyn-GA. (DOCX 71 KB)12936_2011_2083_MOESM1_ESM.DOCX
Authors’ original file for figure 112936_2011_2083_MOESM2_ESM.pdf
Authors’ original file for figure 212936_2011_2083_MOESM3_ESM.ppt
Authors’ original file for figure 312936_2011_2083_MOESM4_ESM.jpeg
Authors’ original file for figure 412936_2011_2083_MOESM5_ESM.ppt
Authors’ original file for figure 512936_2011_2083_MOESM6_ESM.pdf
Authors’ original file for figure 612936_2011_2083_MOESM7_ESM.pdf
Epstein JE, Giersing B, Mullen G, Moorthy V, Richie TL: Malaria vaccines: are we getting closer?. Curr Opin Mol Ther. 2007, 9: 12-24. PubMed
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B: Genome sequence of the human malaria parasite Plasmodium falciparum. Nature. 2002, 419: 498-511. 10.1038/nature01097. CrossRefPubMed
Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B, Russell B, Seitz P, Plouffe DM, Dharia NV, Tan J, Cohen SB, Spencer KR, González-Páez GE, Lakshminarayana SB, Goh A, Suwanarusk R, Jegla T, Schmitt EK, Beck HP, Brun R, Nosten F, Renia L, Dartois V, Keller TH, Fidock DA, Winzeler EA, Diagana TT: Spiroindolones, a potent compound class for the treatment of malaria. Science. 2010, 329: 1175-1180. 10.1126/science.1193225. PubMedCentralCrossRefPubMed
DeBoer C, Meulman PA, Wnuk RJ, Peterson DH: Geldanamycin, a new antibiotic. J Antibiot (Tokyo). 1970, 23: 442-447. 10.7164/antibiotics.23.442. CrossRef
Li LH, Clark TD, Cowie CH, Rinehart KL: Effects of geldanamycin and its derivatives on RNA-directed DNA polymerase and infectivity of Rauscher leukemia virus. Cancer Treat Rep. 1977, 61: 815-824. PubMed
Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM: Inhibition of heat shock protein HSP90-pp 60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA. 1994, 91: 8324-8328. 10.1073/pnas.91.18.8324. PubMedCentralCrossRefPubMed
Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH, Thomas R, Szabo E, Grochow L, Grollman F, Hamilton JM, Neckers L, Wilson RH: Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol. 2005, 23: 1885-1893. 10.1200/JCO.2005.12.085. CrossRefPubMed
Swardson-Olver CJ, Dawson TC, Burnett RC, Peiper SC, Maeda N, Avery AC: Plasmodium yoelii uses the murine Duffy antigen receptor for chemokines as a receptor for normocyte invasion and an alternative receptor for reticulocyte invasion. Blood. 2002, 99: 2677-2684. 10.1182/blood.V99.8.2677. CrossRefPubMed
Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S, Workman P, Judson I: Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. 2005, 23: 4152-4161. 10.1200/JCO.2005.00.612. CrossRefPubMed
Goetz MP, Erlichman C, Windebank AJ, Reid JM, Sloan JA, Atherton P, Adjei AA, Rubin J, Pitot H, Galanis E, Ames MM, Goldberg RM: Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors. J Clin Oncol. 2003, 21: 3761-3769. 10.1200/JCO.2003.01.238. CrossRefPubMed
Roestenberg M, Teirlinck AC, McCall MB, Teelen K, Makamdop KN, Wiersma J, Arens T, Beckers P, van Gemert G, van de Vegte-Bolmer M, van der Ven AJ, Luty AJ, Hermsen CC, Sauerwein RW: Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet. 2011, 377: 1770-1776. 10.1016/S0140-6736(11)60360-7. CrossRefPubMed
Otsuki H, Kaneko O, Thongkukiatkul A, Tachibana M, Iriko H, Takeo S, Tsuboi T, Torii M: Single amino acid substitution in Plasmodium yoelii erythrocyte ligand determines its localization and controls parasite virulence. Proc Natl Acad Sci USA. 2009, 106: 7167-7172. 10.1073/pnas.0811313106. PubMedCentralCrossRefPubMed
Yoeli M, Hargreaves B, Carter R, Walliker D: Sudden increase in virulence in a strain of Plasmodium berghei yoelii. Ann Trop Med Parasitol. 1975, 69: 173-178. PubMed
- Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii
Angela K H Wolf
Vincent Jo Davisson
Gotam K Jarori
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II