A-HERO - Antihelmintic Research and Optimisation

A-HERO brings together different streams of advanced scientific inquiry, ranging from drug discovery to drug development and combines them in a logical way. The project aims at advancing drug options against schistosomiasis and soil-transmitted helminthiases. Several steps along the drug discovery pipeline are covered: in vivo and vitro studies of compound libraries and repurposed drugs, pharmacokinetic and -dynamic studies and exploratory clinical trials for efficacy and safety assessment. The project will furthermore contribute valuable insights into anthelminthic drug assay development and diagnostics. With the application of novel approaches in the field of drug discovery and preclinical development, the project will lay a strong foundation in anthelminthic research and guide and optimize subsequent drug development.

Liu Z, Xia B, Saric J, Utzinger J, Holmes E, Keiser J, Li J.V. Effects of vancomycin and ciprofloxacin on the NMRI mouse metabolism. J Proteome Res. 2018;17(10):3565-3573. DOI: 10.1021/acs.jproteome.8b00583

Meister I, Ingram-Sieber K, Cowan N, Todd M, Robertson M.N, Meli C, Patra M, Gasser G, Keiser J. Activity of praziquantel enantiomers and main metabolites against Schistosoma mansoni. Antimicrob Agents Chemother. 2014;58(9):5466-5472. DOI: 10.1128/AAC.02741-14

Panic G, Flores D, Ingram-Sieber K, Keiser J. Fluorescence/luminescence-based markers for the assessment of Schistosoma mansoni schistosomula drug assays. Parasit Vectors. 2015;8:624. DOI: 10.1186/s13071-015-1233-3

Panic G, Vargas M, Scandale I, Keiser J. Activity profile of an FDA-approved compound library against Schistosoma mansoni. PLoS Negl Trop Dis. 2015;9(7):e0003962. DOI: 10.1371/journal.pntd.0003962

Cowan N, Keiser J. Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni. Parasit Vectors. 2015;8:417. DOI: 10.1186/s13071-015-1023-y

Vejzagic N, Adelfio R, Keiser J, Kringel H, Thamsborg S.M, Kapel C.M. Bacteria-induced egg hatching differs for Trichuris muris and Trichuris suis. Parasit Vectors. 2015;8:371. DOI: 10.1186/s13071-015-0986-z

Keiser J, Vargas M, Rubbiani R, Gasser G, Biot C. In vitro and in vivo antischistosomal activity of ferroquine derivatives. Parasit Vectors. 2014;7:424. DOI: 10.1186/1756-3305-7-424

Flores D, Panic G, Braissant O, Keiser J. A novel isothermal microcalorimetry tool to assess drug effects on Ancylostoma ceylanicum and Necator americanus. Appl Microbiol Biotechnol. 2016;100(2):837-846. DOI: 10.1007/s00253-015-7081-4

Keiser J. Is Caenorhabditis elegans the magic bullet for anthelminthic drug discovery?. Trends Parasitol. 2015;31(10):455-456. DOI: 10.1016/j.pt.2015.08.004

Hess J, Keiser J, Gasser G. Toward organometallic antischistosomal drug candidates. Future Med Chem. 2015;7(6):821-830. DOI: 10.4155/fmc.15.22

Cowan N, Yaremenko I.A, Krylov I, Terent'ev A.O, Keiser J. Elucidation of the in vitro and in vivo activities of bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives against Schistosoma mansoni.. Bioorg Med Chem. 2015;23(16):5175-5181. DOI: 10.1016/j.bmc.2015.02.010

Keiser J, Panic G, Vargas M, Wang C, Dong Y, Gautam N, Vennerstrom J.L. Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal. J Antimicrob Chemother. 2015;70(6):1788-1797. DOI: 10.1093/jac/dkv016

Spivak A.Y, Keiser J, Vargas M, Gubaidullin R.R, Nedopekina D.A, Shakurova E.R, Khalitova R.R, Odinokov V.N. Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo. Bioorg Med Chem. 2014;22(21):6297-6304. DOI: 10.1016/j.bmc.2014.07.014

Panic G, Duthaler U, Speich B, Keiser J. Repurposing drugs for the treatment and control of helminth infections. Int J Parasitol Drugs Drug Resist. 2014;4:185-200. DOI: 10.1016/j.ijpddr.2014.07.002

Keiser J, Panic G, Adelfio R, Cowan N, Vargas M, Scandale I. Evaluation of an FDA approved library against laboratory models of human intestinal nematode infections. Parasit Vectors. 2016;9:376. DOI: 10.1186/s13071-016-1616-0

Wang C, Zhao Q, Vergas M, Jones J.O, White K.L, Shackleford D.M, Chen G, Saunders J, Ng A.C.F, Chiu F.C.K, Dong Y, Charman S.A, Keiser J, Vennerstrom J.L. Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). J Med Chem. 2016;59:10705-10718. DOI: 10.1021/acs.jmedchem.6b01410

Cowan N, Vargas M, Keiser J. In vitro and in vivo drug interaction study of two lead combinations, oxantel pamoate plus albendazole and albendazole plus mebendazole, for the treatment of soil-transmitted helminthiasis. Antimicrob Agents Chemother. 2016;60(10):6127-6133. DOI: 10.1128/AAC.01217-16

Cowan N, Raimondo A, Keiser J. Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity. Parasitol Res. 2016;115(11):4443-4446. DOI: 10.1007/s00436-016-5225-9

Barda B, Coulibaly J.T, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy and safety of moxidectin, synriam, synriam-praziquantel versus praziquantel against Schistosoma haematobium and S. mansoni infections: a randomized, exploratory phase 2 trial. PLoS Negl Trop Dis. 2016;10(9):e0005008. DOI: 10.1371/journal.pntd.0005008

Lo N.C, Coulibaly J.T, Bendavid E, N'Goran E.K, Utzinger J, Keiser J, Bogoch II, Andrews J.R. Evaluation of a urine pooling strategy for the rapid and cost-efficient prevalence classification of schistosomiasis. PLoS Negl Trop Dis. 2016;10(8):e0004894. DOI: 10.1371/journal.pntd.0004894

Qian M.-B, Utzinger J, Keiser J, Zhou X.-N. Clonorchiasis. Lancet. 2016;387(10020):800-810. DOI: 10.1016/S0140-6736(15)60313-0

Speich B, Croll D, Fürst T, Utzinger J, Keiser J. Effect of sanitation and water treatment on intestinal protozoa infection: a systematic review and meta-analysis. Lancet Infect Dis. 2016;16(1):87-99. DOI: 10.1016/S1473-3099(15)00349-7

Meister I, Leonidova A, Kovac J, Duthaler U, Keiser J, Hawyler J. Development and validation of an enantioselective LM-MS/MS method for the analysis of the anthelmintic drug praziquantel and its main metabolite in human plasma, blood and dried blood spots. J Pharm Biomed Anal. 2016;118:81-88. DOI: 10.1016/j.jpba.2015.10.011

Meister I, Kovac J, Duthaler U, Odermatt P, Huwyler J, Vanobberghen F, Sayasone S, Keiser J. Pharmacokinetic study of praziquantel enantiomers and its main metabolite R-trans-4-OH-PZQ in plasma, blood and dried blood spots in Opisthorchis viverrini-infected patients. PLoS Negl Trop Dis. 2016;10(5):e0004700. DOI: 10.1371/journal.pntd.0004700

Clède S, Cowan N, Lambert F, Bertrand H.C, Rubbiani R, Patra M, Hess J, Sandt C, Trcera N, Gasser G, Keiser J, Policar C. Bimodal X-ray and infrared imaging of an organometallic derivative of praziquantel in Schistosoma mansoni. Chembiochem. 2016;17(11):1004-1007. DOI: 10.1002/cbic.201500688

Khan M.O, Keiser J, Amoyaw P.N, Hossain M.F, Vargas M, Le J.G, Simpson N.C, Roewe K.D, Freeman T.N, Hasley T.R, Maples R.D, Archibald S.J, Hubin T.J. Discovery of antischistosomal drug leads based on tetraazamacrocyclic derivatives and their metal complexes. Antimicrob Agents Chemother. 2016;60(9):5331-5336. DOI: 10.1128/AAC.00778-16

Cowan N, Datwyler P, Ernst B, Wang C, Vennerstrom J.L, Spangenberg T, Keiser J. Activities of N,N' -diarylurea MMV665852 analogs against Schistosoma mansoni. Antimicrob Agents Chemother. 2015;59(4):1935-1941. DOI: 10.1128/AAC.04463-14

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