Publications

Hellingman A, Sifoniou K, Buser T, Thommen B.T, Walz A, Passecker A, Collins J, Hupfeld M, Wittlin S, Witmer K, Brancucci N.M.B. Next generation chemiluminescent probes for antimalarial drug discovery. ACS Infect Dis. 2024(in press). DOI: 10.1021/acsinfecdis.3c00707

Mambwe D, Coertzen D, Leshabane M, Mulubwa M, Njoroge M, Gibhard L, Girling G, Wicht K.J, Lee M.C.S, Wittlin S, Moreira D.R.M, Birkholtz L.M, Chibale K. hERG, plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole. ACS Med Chem Lett. 2024(in press). DOI: 10.1021/acsmedchemlett.3c00496

Nguyen W, Boulet C, Dans M.G, Loi K, Jarman K.E, Watson G.M, Tham W.H, Fairhurst K.J, Yeo T, Fidock D.A, Wittlin S, Chowdury M, de Koning-Ward T.F, Chen G, Yan D, Charman S.A, Baud D, Brand S, Jackson P.F, Cowman A.F, Gilson P.R, Sleebs B.E. Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein. Eur J Med Chem. 2024;270:116354. DOI: 10.1016/j.ejmech.2024.116354

Davies H, Bergmann B, Walloch P, Nerlich C, Hansen C, Wittlin S, Spielmann T, Treeck M, Beitz E. The Plasmodium lactate/H+ transporter PfFNT is essential and druggable in vivo. Antimicrob Agents Chemother. 2023;67(8):e0035623. DOI: 10.1128/aac.00356-23

Imlay L.S, Lawong A.K, Gahalawat S, Kumar A, Xing C, Mittal N, Wittlin S, Churchyard A, Niederstrasser H, Crespo-Fernandez B, Posner B.A, Gamo F.J, Baum J, Winzeler E.A, Laleu B, Ready J.M, Phillips M.A. Fast-killing tyrosine amide ((S)-SW228703) with blood- and liver-stage antimalarial activity associated with the cyclic amine resistance locus (PfCARL). ACS Infect Dis. 2023;9(3):527-539. DOI: 10.1021/acsinfecdis.2c00527

Ling D.B, Nguyen W, Looker O, Razook Z, McCann K, Barry A.E, Scheurer C, Wittlin S, Famodimu M.T, Delves M.J, Bullen H.E, Crabb B.S, Sleebs B.E, Gilson P.R. A pyridyl-furan series developed from the Open Global Health Library block red blood cell invasion and protein trafficking in Plasmodium falciparum through potential inhibition of the parasite's PI4KIIIB enzyme. ACS Infect Dis. 2023;9(9):1695-1710. DOI: 10.1021/acsinfecdis.3c00138

Mäser P, Bernhard S, Brun R, Burri C, Gagneux S, Hetzel M.W, Kaiser M, Lengeler C, Pluschke G, Reus E, Rottmann M, Utzinger J, Warryn L, Wittlin S, Keiser J. Key contributions by the Swiss Tropical and Public Health Institute towards new and better drugs for tropical diseases. Chimia (Aarau). 2023;77(9):593-606. DOI: 10.2533/chimia.2023.593

Nguyen W, Dans M.G, Currie I, Awalt J.K, Bailey B.L, Lumb C, Ngo A, Favuzza P, Palandri J, Ramesh S, Penington J, Jarman K.E, Mukherjee P, Chakraborty A, Maier A.G, van Dooren G.G, Papenfuss T, Wittlin S, Churchyard A, Baum J, Winzeler E.A, Baud D, Brand S, Jackson P.F, Cowman A.F, Sleebs B.E. 7-N-substituted-3-oxadiazole quinolones with potent antimalarial activity target the cytochrome bc1 complex. ACS Infect Dis. 2023;9(3):668-691. DOI: 10.1021/acsinfecdis.2c00607

Ren R, Wang X, Leas D.A, Scheurer C, Hövel S, Cal M, Chen G, Zhong L, Katneni K, Pham T, Patil R, Sil D, Walters M.J, Schulze T.T, Neville A.J, Dong Y, Wittlin S, Kaiser M, Davis P.H, Charman S.A, Vennerstrom J.L. Antimalarial dibenzannulated medium-ring keto lactams. ACS Infect Dis. 2023;9(10):1964-1980. DOI: 10.1021/acsinfecdis.3c00245

Walz A, Duffey M, Aljayyoussi G, Sax S, Leroy D, Besson A, Burrows J.N, Cherkaoui-Rbati M.H, Gobeau N, Westwood M-A, Siethoff C, Gamo S, Mäser P, Wittlin S. The Parasite Reduction Ratio (PRR) assay version 2: standardized assessment of Plasmodium falciparum viability after antimalarial treatment in vitro. Pharmaceuticals (Basel). 2023;16(2):163. DOI: 10.3390/ph16020163

de Vries L.E, Jansen P.A.M, Barcelo C, Munro J, Verhoef J.M.J, Pasaje C.F.A, Rubiano K, Striepen J, Abla N, Berning L, Bolscher J.M, Demarta-Gatsi C, Henderson R.W.M, Huijs T, Koolen K.M.J, Tumwebaze P.K, Yeo T, Aguiar A.C.C, Angulo-Barturen I, Churchyard A, Baum J, Fernandez B.C, Fuchs A, Gamo F.J, Guido R.V.C, Jimenez-Diaz M.B, Pereira D.B, Rochford R, Roesch C, Sanz L.M, Trevitt G, Witkowski B, Wittlin S, Cooper R.A, Rosenthal P.J, Sauerwein R.W, Schalkwijk J, Hermkens P.H.H, Bonnert R.V, Campo B, Fidock D.A, Llinas M, Niles J.C, Kooij T.W.A, Dechering K.J. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. Nat Commun. 2022;13:2158. DOI: 10.1038/s41467-022-29688-5

Dong Y, Sonawane Y, Maher S.P, Zeeman A.M, Chaumeau V, Vantaux A, Cooper C.A, Chiu F.C.K, Ryan E, McLaren J, Chen G, Wittlin S, Witkowski B, Nosten F, Sriraghavan K, Kyle D.E, Kocken C.H.M, Charman S.A, Vennerstrom J.L. Metabolic, pharmacokinetic, and activity profile of the liver stage antimalarial (RC-12). ACS Omega. 2022;7(14):12401-12411. DOI: 10.1021/acsomega.2c01099

Laleu B, Rubiano K, Yeo T, Hallyburton I, Anderson M, Crespo-Fernandez B, Gamo F.J, Antonova-Koch Y, Orjuela-Sanchez P, Wittlin S, Jana G.P, Maity B.C, Chenu E, Duffy J, Sjö P, Waterson D, Winzeler E, Guantai E, Fidock D.A, Hansson T. Exploring a tetrahydroquinoline antimalarial hit from the medicines for malaria pathogen box and the identification of its mode of resistance as PfeEF2. ChemMedChem. 2022;17(22):e202200393. DOI: 10.1002/cmdc.202200393

Lowe M.A, Cardenas A, Valentin J.P, Zhu Z, Abendroth J, Castro J.L, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer D.D, MacCoss M, Rowley J.H, Rosseels M.L, Royer L, Taylor R.D, Wong M, Zaccheo O, Chavan V.P, Ghule G.A, Tapkir B.K, Burrows J.N, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jiménez-Díaz M.B, Striepen J, Fairhurst K.J, Yeo T, Fidock D.A, Cowman A.F, Favuzza P, Crespo-Fernandez B, Gamo F.J, Goldberg D.E, Soldati-Favre D, Laleu B, de Haro T. Discovery and characterization of potent, efficacious, orally available antimalarial plasmepsin X inhibitors and preclinical safety assessment of UCB7362. J Med Chem. 2022;65(20):14121-14143. DOI: 10.1021/acs.jmedchem.2c01336

Mambwe D, Korkor CM, Mabhula A, Ngqumba Z, Cloete C, Kumar M, Barros PL, Leshabane M, Coertzen D, Taylor D, Gibhard L, Njoroge M, Lawrence N, Reader J, Moreira DR, Birkholtz LM, Wittlin S, Egan TJ, Chibale K. Novel 3-trifluoromethyl-1,2,4-oxadiazole analogues of astemizole with multi-stage antiplasmodium activity and in vivo efficacy in a Plasmodium berghei mouse malaria infection model. J Med Chem. 2022;65(24):16695-16715. DOI: 10.1021/acs.jmedchem.2c01516

Xie S.C, Metcalfe R.D, Dunn E, Morton C.J, Huang S.C, Puhalovich T, Du Y, Wittlin S, Nie S, Luth M.R, Ma L, Kim M.S, Pasaje C.F.A, Kumpornsin K, Giannangelo C, Houghton F.J, Churchyard A, Famodimu M.T, Barry D.C, Gillett D.L, Dey S, Kosasih C.C, Newman W, Niles J.C, Lee M.C.S, Baum J, Ottilie S, Winzeler E.A, Creek D.J, Williamson N, Parker M.W, Brand S, Langston S.P, Dick L.R, Griffin M.D.W, Gould A.E, Tilley L. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy. Science. 2022;376(6597):1074-1079. DOI: 10.1126/science.abn0611

Boss C, Wittlin S. Our exciting journey to ACT-451840. Chimia. 2021;75(11):916-922. DOI: 10.2533/chimia.2021.916

Cheuka P.M, Centani L, Arendse L.B, Fienberg S, Wambua L, Renga S.S, Dziwornu G.A, Kumar M, Lawrence N, Taylor D, Wittlin S, Coertzen D, Reader J, van der Watt M, Birkholtz L.M, Chibale K. New amidated 3,6-diphenylated imidazopyridazines with potent antiplasmodium activity are dual inhibitors of Plasmodium phosphatidylinositol-4-kinase and cGMP-dependent protein kinase. ACS Infect Dis. 2021;7(1):34-46. DOI: 10.1021/acsinfecdis.0c00481

Dziwornu G.A, Coertzen D, Leshabane M, Korkor C.M, Cloete C.K, Njoroge M, Gibhard L, Lawrence N, Reader J, van der Watt M, Wittlin S, Birkholtz L.M, Chibale K. Antimalarial benzimidazole derivatives incorporating phenolic mannich base side chains inhibit microtubule and hemozoin formation: structure-activity relationship and in vivo oral efficacy studies. J Med Chem. 2021;64(8):5198–5215. DOI: 10.1021/acs.jmedchem.1c00354

Hitz E, Grüninger O, Passecker A, Wyss M, Scheurer C, Wittlin S, Beck H.P, Brancucci N.M.B, Voss T.S. The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis. Commun Biol. 2021;4(1):336. DOI: 10.1038/s42003-021-01873-0

Hitz E, Wiedemar N, Passecker A, Graça B.A.S, Scheurer C, Wittlin S, Brancucci N.M.B, Vakonakis I, Mäser P, Voss T.S. The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites. PLoS Biol. 2021;19(12):e3001483. DOI: 10.1371/journal.pbio.3001483

Knaab T.C, Held J, Burckhardt B.B, Rubiano K, Okombo J, Yeo T, Mok S, Uhlemann A.C, Lungerich B, Fischli C, Pessanha de Carvalho L, Mordmüller B, Wittlin S, Fidock D.A, Kurz T. 3-Hydroxy-propanamidines, a new class of orally active antimalarials targeting Plasmodium falciparum. J Med Chem. 2021;64(6):3035-3047. DOI: 10.1021/acs.jmedchem.0c01744

Laleu B, Akao Y, Ochida A, Duffy S, Lucantoni L, Shackleford D.M, Chen G, Katneni K, Chiu F.C.K, White K.L, Chen X, Sturm A, Dechering K.J, Crespo B, Sanz L.M, Wang B, Wittlin S, Charman S.A, Avery V.M, Cho N, Kamaura M. Discovery and structure-activity relationships of quinazolinone-2-carboxamide derivatives as novel orally efficacious antimalarials. J Med Chem. 2021;64(17):12582-12602. DOI: 10.1021/acs.jmedchem.1c00441

Lawong A, Gahalawat S, Okombo J, Striepen J, Yeo T, Mok S, Deni I, Bridgford J.L, Niederstrasser H, Zhou A, Posner B, Wittlin S, Gamo F.J, Crespo B, Churchyard A, Baum J, Mittal N, Winzeler E, Laleu B, Palmer M.J, Charman S.A, Fidock D.A, Ready J.M, Phillips M.A. Novel antimalarial tetrazoles and amides active against the hemoglobin degradation pathway in Plasmodium falciparum. J Med Chem. 2021;64(5):2739-2761. DOI: 10.1021/acs.jmedchem.0c02022

Le Manach C, Dam J, Woodland J.G, Kaur G, Khonde L.P, Brunschwig C, Njoroge M, Wicht K.J, Horatscheck A, Paquet T, Boyle G.A, Gibhard L, Taylor D, Lawrence N, Yeo T, Mok S, Eastman R.T, Dorjsuren D, Talley D.C, Guo H, Simeonov A, Reader J, van der Watt M, Erlank E, Venter N, Zawada J.W, Aswat A, Nardini L, Coetzer T.L, Lauterbach S.B, Bezuidenhout B.C, Theron A, Mancama D, Koekemoer L.L, Birkholtz L.M, Wittlin S, Delves M, Ottilie S, Winzeler E.A, von Geldern T.W, Smith D, Fidock D.A, Street L.J, Basarab G.S, Duffy J, Chibale K. Identification and profiling of a novel diazaspiro[3.4]octane chemical series active against multiple stages of the human malaria parasite Plasmodium falciparum and optimization efforts. J Med Chem. 2021;64(4):2291-2309. DOI: 10.1021/acs.jmedchem.1c00034

Leas D.A, Sanford A.G, Wu J, Cal M, Kaiser M, Wittlin S, Hemsley R.M, Darner E.B, Lui L.M, Davis P.H, Vennerstrom J.L. Diaryl ureas as an antiprotozoal chemotype. ACS Infect Dis. 2021;7(6):1578-1583. DOI: 10.1021/acsinfecdis.1c00135

Murithi J.M, Pascal C, Bath J, Boulenc X, Gnadig N.F, Pasaje C.F.A, Rubiano K, Yeo T, Mok S, Klieber S, Desert P, Jimenez-Diaz M.B, Marfurt J, Rouillier M, Cherkaoui-Rbati M.H, Gobeau N, Wittlin S, Uhlemann A.C, Price R.N, Wirjanata G, Noviyanti R, Tumwebaze P, Cooper R.A, Rosenthal P.J, Sanz L.M, Gamo F.J, Joseph J, Singh S, Bashyam S, Augereau J.M, Giraud E, Bozec T, Vermat T, Tuffal G, Guillon J.M, Menegotto J, Salle L, Louit G, Cabanis M.J, Nicolas M.F, Doubovetzky M, Merino R, Bessila N, Angulo-Barturen I, Baud D, Bebrevska L, Escudie F, Niles J.C, Blasco B, Campbell S, Courtemanche G, Fraisse L, Pellet A, Fidock D.A, Leroy D. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance. Sci Transl Med. 2021;13(603):eabg6013. DOI: 10.1126/scitranslmed.abg6013

Okaniwa M, Shibata A, Ochida A, Akao Y, White K.L, Shackleford D.M, Duffy S, Lucantoni L, Dey S, Striepen J, Yeo T, Mok S, Aguiar A.C.C, Sturm A, Crespo B, Sanz L.M, Churchyard A, Baum J, Pereira D.B, Guido R.V.C, Dechering K.J, Wittlin S, Uhlemann A.C, Fidock D.A, Niles J.C, Avery V.M, Charman S.A, Laleu B. Repositioning and characterization of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives as Plasmodium cytoplasmic prolyl-trna synthetase inhibitors. ACS Infect Dis. 2021;7(6):1680-1689. DOI: 10.1021/acsinfecdis.1c00020

Palmer M.J, Deng X, Watts S, Krilov G, Gerasyuto A, Kokkonda S, El Mazouni F, White J, White K.L, Striepen J, Bath J, Schindler K.A, Yeo T, Shackleford D.M, Mok S, Deni I, Lawong A, Huang A, Chen G, Wang W, Jayaseelan J, Katneni K, Patil R, Saunders J, Shahi S.P, Chittimalla R, Angulo-Barturen I, Jimenez-Diaz M.B, Wittlin S, Tumwebaze P.K, Rosenthal P.J, Cooper R.A, Aguiar A.C.C, Guido R.V.C, Pereira D.B, Mittal N, Winzeler E.A, Tomchick D.R, Laleu B, Burrows J.N, Rathod P.K, Fidock D.A, Charman S.A, Phillips M.A. Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series. J Med Chem. 2021;64(9):6085-6136. DOI: 10.1021/acs.jmedchem.1c00173

Shackleford D.M, Chiu F.C.K, Katneni K, Blundell S, McLaren J, Wang X, Zhou L, Sriraghavan K, Alker A.M, Hunziker D, Scheurer C, Zhao Q, Dong Y, Mohrle J.J, Abla N, Matile H, Wittlin S, Vennerstrom J.L, Charman S.A. Cytochrome P450-mediated metabolism and CYP Inhibition for the synthetic peroxide antimalarial OZ439. ACS Infect Dis. 2021;7(7):1885-1893. DOI: 10.1021/acsinfecdis.1c00225

Wittlin S, Mäser P. From magic bullet to magic bomb: reductive bioactivation of antiparasitic agents. ACS Infect Dis. 2021;7(10):2777-2786. DOI: 10.1021/acsinfecdis.1c00118

Xie S.C, Metcalfe R.D, Mizutani H, Puhalovich T, Hanssen E, Morton C.J, Du Y, Dogovski C, Huang S.C, Ciavarri J, Hales P, Griffin R.J, Cohen L.H, Chuang B.C, Wittlin S, Deni I, Yeo T, Ward K.E, Barry D.C, Liu B, Gillett D.L, Crespo-Fernandez B.F, Ottilie S, Mittal N, Churchyard A, Ferguson D, Aguiar A.C.C, Guido R.V.C, Baum J, Hanson K.K, Winzeler E.A, Gamo F.J, Fidock D.A, Baud D, Parker M.W, Brand S, Dick L.R, Griffin M.D.W, Gould A.E, Tilley L. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. Proc Natl Acad Sci U S A. 2021;118(39):e2107213118. DOI: 10.1073/pnas.2107213118

Ahenkorah S, Coertzen D, Tong J.X, Fridianto K, Wittlin S, Birkholtz L.M, Tan K.S.W, Lam Y, Go M.L, Haynes R.K. Antimalarial N1,N3-dialkyldioxonaphthoimidazoliums: synthesis, biological activity, and structure-activity relationships. ACS Med Chem Lett. 2020;11:49-55. DOI: 10.1021/acsmedchemlett.9b00457

Burgert L, Rottmann M, Wittlin S, Gobeau N, Krause A, Dingemanse J, Möhrle J.J, Penny M.A. Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development. Sci Rep. 2020;10:4410. DOI: 10.1038/s41598-020-61304-8

Horatscheck A, Andrijevic A, Nchinda A.T, Le Manach C, Paquet T, Khonde L.P, Dam J, Pawar K, Taylor D, Lawrence N, Brunschwig C, Gibhard L, Njoroge M, Reader J, van der Watt M, Wicht K, de Sousa A.C.C, Okombo J, Maepa K, Egan T.J, Birkholtz L.M, Basarab G.S, Wittlin S, Fish P.V, Street L.J, Duffy J, Chibale K. Identification of 2,4-disubstituted imidazopyridines as hemozoin formation inhibitors with fast-killing kinetics and in vivo efficacy in the Plasmodium falciparum NSG mouse model. J Med Chem. 2020;63(21):13013-13030. DOI: 10.1021/acs.jmedchem.0c01411

Kokkonda S, Deng X, White K.L, El Mazouni F, White J, Shackleford D.M, Katneni K, Chiu F.C.K, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz M.B, Ferrer S, Huertas-Valentin L, Martinez-Martinez M.S, Lafuente-Monasterio M.J, Chittimalla R, Shahi S.P, Wittlin S, Waterson D, Burrows J.N, Matthews D, Tomchick D, Rathod P.K, Palmer M.J, Charman S.A, Phillips M.A. Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria. J Med Chem. 2020;63(9):4929-4956. DOI: 10.1021/acs.jmedchem.0c00311

Potluri V, Shandil R.K, Gavara R, Sambasivam G, Campo B, Wittlin S, Narayanan S. Discovery of FNDR-20123, a histone deacetylase inhibitor for the treatment of Plasmodium falciparum malaria. Malar J. 2020;19:365. DOI: 10.1186/s12936-020-03421-3

Attram H.D, Wittlin S, Chibale K. Incorporation of an intramolecular hydrogen bonding motif in the side chain of antimalarial benzimidazoles. MedChemComm. 2019;10(3):450-455. DOI: 10.1039/c8md00608c

Baartzes N, Stringer T, Seldon R, Warner D.F, Taylor D, Wittlin S, Chibale K, Smith G.S. Bioisosteric ferrocenyl aminoquinoline-benzimidazole hybrids: antimicrobial evaluation and mechanistic insights. Eur J Med Chem. 2019;180:121-133. DOI: 10.1016/j.ejmech.2019.06.069

Baragaña B, Forte B, Choi R, Nakazawa Hewitt S, Bueren-Calabuig J.A, Pisco J.P, Peet C, Dranow D.M, Robinson D.A, Jansen C, Norcross N.R, Vinayak S, Anderson M, Brooks C.F, Cooper C.A, Damerow S, Delves M, Dowers K, Duffy J, Edwards T.E, Hallyburton I, Horst B.G, Hulverson M.A, Ferguson L, Jiménez-Díaz M.B, Jumani R.S, Lorimer D.D, Love M.S, Maher S, Matthews H, McNamara C.W, Miller P, O'Neill S, Ojo K.K, Osuna-Cabello M, Pinto E, Post J, Riley J, Rottmann M, Sanz L.M, Scullion P, Sharma A, Shepherd S.M, Shishikura Y, Simeons F.R.C, Stebbins E.E, Stojanovski L, Straschil U, Tamaki F.K, Tamjar J, Torrie L.S, Vantaux A, Witkowski B, Wittlin S, Yogavel M, Zuccotto F, Angulo-Barturen I, Sinden R, Baum J, Gamo F.J, Mäser P, Kyle D.E, Winzeler E.A, Myler P.J, Wyatt P.G, Floyd D, Matthews D, Sharma A, Striepen B, Huston C.D, Gray D.W, Fairlamb A.H, Pisliakov A.V, Walpole C, Read K.D, Van Voorhis W.C, Gilbert I.H. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc Natl Acad Sci USA. 2019;116(14):7015-7020. DOI: 10.1073/pnas.1814685116