Abstract
Schistosomiasis, a parasitic disease caused by infection by helminths of the Schistosoma genus, affects over 200 million people, primarily in the developing world. Treatment of this disease largely relies on one drug, praziquantel. Although this drug is cheap, safe, and effective, the looming prospect of drug resistance makes the development of a pipeline of anti-schistosomiasis drugs a priority. Many new drug leads have arisen from screening existing sets of compounds such as the Open Access Boxes developed by the Medicines for Malaria Venture (MMV) in collaboration with the Drugs for Neglected Diseases Initiative (DNDI). Other leads have been found through work focused on druggable targets such as kinases, histone deacetylases, proteases, and others. This chapter will discuss recent work concerning the discovery and development of novel anti-schistosomiasis drug leads from many sources.
Keywords
- schistosomiasis
- drug discovery
- praziquantel
- antiparasitic medicinal chemistry
- drug screening
- enzyme inhibitors
1. Introduction
Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people, primarily in the developing world [1, 2]. The disease is caused by blood flukes of the genus
Chronic schistosomiasis is associated with diseases of the kidneys, spleen, liver, bladder and intestine [3]. In endemic areas, up to 75% of the incidence of bladder cancer has been attributed to infection with
Current treatment of this disease relies almost exclusively on one drug: praziquantel (
2. Praziquantel
In 1972, Merck and Bayer tested
Since
3. Oxamniquine
The development of oxamniquine (
Although
Ferrocenyl and ruthenocenyl derivatives of
4. Antischistosomal antimalarials
4.1 Artemisinins
Artemisinin (
Artemisinins such as
4.2 Trioxolanes
The success of artemisinins as antiparasitic agents has motivated the development of fully synthetic derivatives [45]. OZ78 (
4.3 Other antimalarials
Other antimalarials, including mefloquine (
Many natural products have demonstrated anti-schistosomiasis activity [10, 50, 51, 52]. The aurone scaffold is another source of antimalarial compounds [53, 54] that has been investigated for anti-schistosomiasis potential [55, 56]. Aurone
Cryptolepines, isolated from the roots of
5. New antischistosomals found by phenotypic screening
5.1 Medium-throughput phenotypic screening results
The diarylurea MMV665852 (
Commercially available analogs of
Further exploration of the diarylurea chemotype resulted in the synthesis and testing of 20 new analogs designed with aqueous solubility and chemical diversity in mind. Seven of these analogs demonstrated sub-micromolar IC50’s against adult
Another of the leads from the Malaria Box screening, the dianilinoquinoxaline MMV007204 (
The MMV Stasis Box, containing 400 compounds that whose development as drugs was stopped at an advanced stage for various reasons, was also explored as a source of new chemotypes for anti-schistosomiasis drug development [69]. Eleven of these compounds showed an
The MMV also prepared a Pathogen Box containing 400 compounds with activity against various neglected diseases, including malaria, tuberculosis, toxoplasmosis, and schistosomiasis. Three institutions explored this compound set for anti-schistosomiasis activity; teams at the Swiss Tropical and Public Health (TPH) [71] and the University of California-San Diego (UCSD) conducted
Notably,
The most recent MMV Box to be assessed for anti-schistosomiasis activity was the Pandemic Response Box, a set of compounds with antibacterial, antiviral and/or antifungal activity [74]. Phenotypic screening found 17 of these 400 compounds to have at least moderate activity (>66%) against adult
Phenotypic screening of a set of 2160 compounds purchased from Microsource Discovery Systems, containing 821 FDA-approved drugs, against
Recently, a set of 73 non-steroidal anti-inflammatory drugs (NSAIDs) was screened for activity against
5.2 High-throughput screening results
Development of reliable high-throughput screening (HTS) tools promises to accelerate the identification of novel anti-schistosomiasis chemotypes [78]. Using a previously developed high-throughput protocol for screening NTS [79], Mansour et al. tested over 294,000 compounds taken from MMV, Pfizer, European Screening Port, GSK (the Tres Cantos Antimalarial Set), and Enamine [80]. The compounds from this set selected for further development, compounds
Several of these leads bear indole or azaindole (e.g., triazolopyridine) units; indoles similar to
Another HTS strategy uses ATP quantitation to assess test compounds’ effect on the number and viability of schistosomula in a sample [84]. Applying this screen to a 40,000-sample set, followed by clustering and retesting, led to compounds
6. Target based approaches
6.1 Targeting thioredoxin glutathione reductase
The redox system of
Auranofin (
Early HTS efforts in this vein revealed the oxadiazole 2-oxide scaffold as a promising lead for novel
HTS efforts to find other
A secondary “doorstop pocket” binding site in
6.2 Targeting kinases
Kinases play critical roles in regulating vital functions like cell proliferation, differentiation, apoptosis, and migration in various organisms. The use of protein-kinase-targeting drugs against
Protein tyrosine kinases (PTKs) are involved in angiogenesis, reproduction, cell proliferation, and many other processes [102]. Many PTK inhibitors (or “tyrphostins”, for tyrosine phosphorylation inhibitors [103]) are able to inhibit multiple PTKs, including receptor tyrosine kinases (RTKs) like growth factor receptors, insulin receptors, (IR) and Venus kinase receptors (VKR). Among the RTK inhibitors that have demonstrated antischistosomal activity is BIBF1120 (
Other kinases that have been studied as antischistosomal targets include mitogen-activated protein kinases (MAPKs) [106, 107], Polo-like kinases (PLKs) [108], Abl-kinase [109], and
6.3 Targeting hemozoin formation
Like other blood-feeding parasites,
A series of pyrido[1,2-
Further investigation of this scaffold led to analogs
6.4 Targeting cysteine proteases
Cysteine proteases are integral to metabolism, nutrition and immune invasion in several parasites, including
6.5 Targeting tubulin
Tubulin, and tubulin-containing cellular components like microtubules, which are essential for cell division and many other functions of the eukaryotic cell, have long been considered druggable targets in
Phenotypic screening of a library of tubulin-binding compounds led to the further exploration of the phenylpyrimidine scaffold as a source of new leads [127]. Further development resulted in thiophene-substituted phenylpyrimidines such as
6.6 Targeting histone deacetylase
Histone deacetylase (HDAC) inhibitors, developed for epigenetic cancer chemotherapy [128], have shown effectiveness against
6.7 Other targets
Other
7. Conclusion
The drawbacks of global schistosomiasis monotherapy with
References
- 1.
McManus DP, Dunne DW, Sacko M, Utzinger J, Vennervald BJ, Zhou X. Schistosomiasis. Nature Reviews Disease Primers. 2018; 4 (1):13 - 2.
Steinmann P, Keiser J, Bos R, Tanner M, Utzinger J. Schistosomiasis and water resources development: Systematic review, meta-analysis, and estimates of people at risk. The Lancet Infectious Diseases. 2006; 6 (7):411-425 - 3.
Gray DJ, Ross AG, Li YS, McManus DP. Diagnosis and management of schistosomiasis. BMJ. 2011; 342 :d2651 - 4.
Van Tong H, Brindley PJ, Meyer CG, Velavan TP. Parasite infection, carcinogenesis and human malignancy. eBioMedicine. 2017; 15 :12-23 - 5.
Bhagwandeen S. Schistosomiasis and carcinoma of the bladder in Zambia. South African Medical Journal. 1976; 50 (41):1616-1620 - 6.
von Bulow V, Lichtenberger J, Grevelding CG, Falcone FH, Roeb E, Roderfeld M. Does Schistosoma Mansoni facilitate carcinogenesis? Cells. 2021;10 (8):1982. DOI: 10.3390/cells10081982 - 7.
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ, editors. Global Burden of Disease and Risk Factors. Washington, DC: World Bank and Oxford University Press; 2006 - 8.
Dziwornu GA, Attram HD, Gachuhi S, Chibale K. Chemotherapy for human schistosomiasis: How far have we come? What’s new? Where do we go from here? RSC Medicinal Chemistry. 2020; 11 (4):455-490 - 9.
Caffrey CR, El-Sakkary N, Mäder P, Krieg R, Becker K, Schlitzer M, et al. Drug discovery and development for schistosomiasis. Neglected Tropical Diseases: Drug Discovery and Development. 2019:187-225 - 10.
Gemma S, Federico S, Brogi S, Brindisi M, Butini S, Campiani G. Dealing with schistosomiasis: Current drug discovery strategies. Annual Reports in Medicinal Chemistry. 2019; 2019 (53):107-138 - 11.
Thétiot-Laurent SA, Boissier J, Robert A, Meunier B. Schistosomiasis chemotherapy. Angewandte Chemie International Edition. 2013; 52 (31):7936-7956 - 12.
Mader P, Rennar GA, Ventura AMP, Grevelding CG, Schlitzer M. Chemotherapy for fighting schistosomiasis: Past, present and future. ChemMedChem. 2018; 13 (22):2374-2389 - 13.
Lago EM, Xavier RP, Teixeira TR, Silva LM, da Silva Filho AA, de Moraes J. Antischistosomal agents: State of art and perspectives. Future Medicinal Chemistry. 2018; 10 (1):89-120 - 14.
Novaes M, Souza JPD, Araújo HCD. Síntese do anti-helmíntico praziquantel, a partir da glicina. Química Nova. 1999; 22 (1):5-10 - 15.
Sinha S, Sharma B. Neurocysticercosis: A review of current status and management. Journal of Clinical Neuroscience. 2009; 16 (7):867-876 - 16.
Guglielmo S, Cortese D, Vottero F, Rolando B, Kommer VP, Williams DL, et al. New praziquantel derivatives containing NO-donor furoxans and related furazans as active agents against Schistosoma mansoni . Eur J Med Chem. 2014;84 :135-145 - 17.
Wang H, Fang Z, Zheng Y, Zhou K, Hu C, Krausz KW, et al. Metabolic profiling of praziquantel enantiomers. Biochemical Pharmacology. 2014; 90 (2):166-178 - 18.
da Silva VBR, Campos BRKL, de Oliveira JF, Decout JL, do Carmo Alves de Lima M. Medicinal chemistry of antischistosomal drugs: Praziquantel and oxamniquine. Bioorganic & Medicinal Chemistry. 2017; 25 (13):3259-3277 - 19.
Patra M, Ingram K, Pierroz V, Ferrari S, Spingler B, Keiser J, et al. Ferrocenyl derivatives of the anthelmintic praziquantel: Design, synthesis, and biological evaluation. Journal of Medicinal Chemistry. 2012; 55 (20):8790-8798 - 20.
Patra M, Ingram K, Pierroz V, Ferrari S, Spingler B, Gasser RB, et al. [(η6-Praziquantel)Cr(CO)3] derivatives with remarkable in vitro antischistosomal activity. Chemistry: A European Journal. 2013;19 (7):2232-2235 - 21.
Patra M, Ingram K, Leonidova A, Pierroz V, Ferrari S, Robertson MN, et al. In vitro metabolic profile andin vivo antischistosomal activity studies of (η6-praziquantel)Cr(CO)3 derivatives. Journal of Medicinal Chemistry. 2013;56 (22):9192-9198 - 22.
Chulkov EG, Smith E, Rohr CM, Yahya NA, Park S, Scampavia L, et al. Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel. PLoS Neglected Tropical Diseases. 2021; 15 (11):e0009898 - 23.
Park SK, Gunaratne GS, Chulkov EG, Moehring F, McCusker P, Dosa PI, et al. The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel. The Journal of Biological Chemistry. 2019; 294 (49):18873-18880 - 24.
Bais S, Greenberg RM. Schistosome TRP channels: An appraisal. International Journal for Parasitology: Drugs and Drug Resistance. 2020; 13 :1-7 - 25.
Bais S, Greenberg RM. TRP channels as potential targets for antischistosomals. International Journal for Parasitology: Drugs and Drug Resistance. 2018; 8 (3):511-517 - 26.
Nilius B, Szallasi A. Transient receptor potential channels as drug targets: From the science of basic research to the art of medicine. Pharmacological Reviews. 2014; 66 (3):676-814 - 27.
Moran MM. TRP channels as potential drug targets. Annual Review of Pharmacology and Toxicology. 2018; 58 :309-330 - 28.
Li S, Westwick J, Poll C. Transient receptor potential (TRP) channels as potential drug targets in respiratory disease. Cell Calcium. 2003; 33 (5-6):551-558 - 29.
Pax R, Bennett J, Fetterer R. A benzodiazepine derivative and praziquantel: Effects on musculature of Schistosoma mansoni andSchistosoma japonicum . Naunyn-Schmiedeberg’s Archives of Pharmacology. 1978;304 (3):309-315 - 30.
Richards HC, Foster R. A new series of 2-aminomethyltetrahydroquinoline derivatives displaying schistosomicidal activity in rodents and primates. Nature. 1969; 222 (5193):581-582 - 31.
Foster R, Cheetham B, King D, Mesmer E. The action of UK 3883, a novel 2-aminomethyltetrahydroquinoline derivative, against mature schistosomes in rodents and primates. Annals of Tropical Medicine and Parasitology. 1971; 65 (1):59-70 - 32.
Kaye B, Woolhouse N. The metabolism of a new schistosomicide 2-isopropylaminomethyl-6-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (UK 3883). Xenobiotica. 1972; 2 (2):169-178 - 33.
Rugel AR, Guzman MA, Taylor AB, Chevalier FD, Tarpley RS, McHardy SF, et al. Why does oxamniquine kill Schistosoma mansoni and notS. haematobium andS. japonicum ? International Journal for Parasitology: Drugs and Drug Resistance. 2020;13 :8-15 - 34.
Valentim CL, Cioli D, Chevalier FD, Cao X, Taylor AB, Holloway SP, et al. Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites. Science. 2013; 342 (6164):1385-1389 - 35.
Taylor AB, Roberts KM, Cao X, Clark NE, Holloway SP, Donati E, et al. Structural and enzymatic insights into species-specific resistance to schistosome parasite drug therapy. The Journal of Biological Chemistry. 2017; 292 (27):11154-11164 - 36.
Guzman MA, Rugel AR, Tarpley RS, Alwan SN, Chevalier FD, Kovalskyy DP, et al. An iterative process produces oxamniquine derivatives that kill the major species of schistosomes infecting humans. PLoS Neglected Tropical Diseases. 2020; 14 (8):e0008517 - 37.
Hess J, Panic G, Patra M, Mastrobuoni L, Spingler B, Roy S, et al. Ferrocenyl, ruthenocenyl, and benzyl oxamniquine derivatives with cross-species activity against Schistosoma mansoni andSchistosoma haematobium . ACS Infectious Diseases. 2017;3 (9):645-652 - 38.
Buchter V, Hess J, Gasser G, Keiser J. Assessment of tegumental damage to Schistosoma mansoni and S.haematobium afterin vitro exposure to ferrocenyl, ruthenocenyl and benzyl derivatives of oxamniquine using scanning electron microscopy. Parasites & Vectors. 2018;11 :580 - 39.
Buchter V, Ong YC, Mouvet F, Ladaycia A, Lepeltier E, Rothlisberger U, et al. Multidisciplinary preclinical investigations on three oxamniquine analogues as new drug candidates for schistosomiasis. Chemistry: A European Journal. 2020; 26 (66):15232-15241 - 40.
Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nature Medicine. 2011; 17 (10):1217-1220 - 41.
Qinghaosu Antimalarial Coordinating Research Group. Antimalarial studies on qinghaosu. Chinese Medical Journal. 1979; 92 :811-816 - 42.
Chen D, Fu L, Shao P, Wu F, Fan C, Shu H, et al. Experimental studies on antischistosomal activity of qinghaosu. Chinese Medical Journal. 1980; 60 :422-425 - 43.
Keiser J, Utzinger J. Antimalarials in the treatment of schistosomiasis. Current Pharmaceutical Design. 2012; 18 (24):3531-3538 - 44.
Bergquist R, Utzinger J, Keiser J. Controlling schistosomiasis with praziquantel: How much longer without a viable alternative? Infectious Diseases of Poverty. 2017; 6 (1):74 - 45.
Panic G, Duthaler U, Speich B, Keiser J. Repurposing drugs for the treatment and control of helminth infections. International Journal for Parasitology: Drugs and Drug Resistance. 2014; 4 (3):185-200 - 46.
Xiao SH, Keiser J, Chollet J, Utzinger J, Dong Y, Endriss Y, et al. In vitro andin vivo activities of synthetic trioxolanes against major human schistosome species. Antimicrobial Agents and Chemotherapy. 2007;51 (4):1440-1445 - 47.
Laurent SA, Boissier J, Coslédan F, Gornitzka H, Robert A, Meunier B. Synthesis of “trioxaquantel”® derivatives as potential new antischistosomal drugs. European Journal of Organic Chemistry. 2008; 2008 (5):895-913 - 48.
Keiser J, Chollet J, Xiao S, Mei J, Jiao P, Utzinger J, et al. Mefloquine—An aminoalcohol with promising antischistosomal properties in mice. PLoS Neglected Tropical Diseases. 2009; 3 (1):e350 - 49.
Koehne E, Zander N, Rodi M, Held J, Hoffmann W, Zoleko-Manego R, et al. Evidence for in vitro andin vivo activity of the antimalarial pyronaridine againstSchistosoma . PLoS Neglected Tropical Diseases. 2021;15 (6):e0009511 - 50.
de Moraes J. Natural products with antischistosomal activity. Future Medicinal Chemistry. 2015; 7 (6):801-820 - 51.
de Carvalho LSA, Silva LM, de Souza VC, da Silva MPN, Capriles PVSZ, de Faria PP, et al. Cardamonin presents in vivo activity againstSchistosoma mansoni and inhibits potato apyrase. Chemistry & Biodiversity. 2021;18 (11):e2100604 - 52.
Simoben CV, Ntie-Kang F, Akone SH, Sippl W. Compounds from African medicinal plants with activities against selected parasitic diseases: Schistosomiasis, trypanosomiasis and leishmaniasis. Natural Products and Bioprospecting. 2018; 8 (3):151-169 - 53.
Carrasco MP, Newton AS, Goncalves L, Gois A, Machado M, Gut J, et al. Probing the aurone scaffold against Plasmodium falciparum : Design, synthesis and antimalarial activity. European Journal of Medicinal Chemistry. 2014;80 :523-534 - 54.
Kayser O, Kiderlen AF, Croft SL. Natural products as antiparasitic drugs. Parasitology Research. 2003; 90 (Suppl. 2):S55-S62 - 55.
Pereira VRD, da Silveira LS, Mengarda AC, Alves Junior IJ, da Silva OOZ, Miguel FB, et al. Antischistosomal properties of aurone derivatives against juvenile and adult worms of Schistosoma mansoni . Acta Tropica. 2021;213 :105741 - 56.
Silva Torres D, Alves de Oliveira B, Souza D, Silveira L, Paulo da Silva M, Rodrigues Duraes Pereira V, et al. Synthetic aurones: New features for Schistosoma mansoni therapy. Chemistry Biodiversity. 2021;18 (11):e2100439 - 57.
Wright CW. Recent developments in naturally derived antimalarials: Cryptolepine analogues. The Journal of Pharmacy and Pharmacology. 2007; 59 (6):899-904 - 58.
El Bardicy S, El Sayed I, Yousif F, Van der Veken P, Haemers A, Augustyns K, et al. Schistosomicidal and molluscicidal activities of aminoalkylamino substituted neo- and norneocryptolepine derivatives. Pharmaceutical Biology. 2012; 50 (2):134-140 - 59.
Marxer M, Ingram K, Keiser J. Development of an in vitro drug screening assay usingSchistosoma haematobium schistosomula. Parasites & Vectors. 2012;5 :165 - 60.
Spangenberg T, Burrows JN, Kowalczyk P, McDonald S, Wells TN, Willis P. The open access malaria box: A drug discovery catalyst for neglected diseases. PLoS One. 2013; 8 (6):e62906 - 61.
Ingram-Sieber K, Cowan N, Panic G, Vargas M, Mansour NR, Bickle QD, et al. Orally active antischistosomal early leads identified from the open access malaria box. PLoS Neglected Tropical Diseases. 2014; 8 (1):e2610 - 62.
Yao H, Liu F, Chen J, Li Y, Cui J, Qiao C. Antischistosomal activity of N, N′-arylurea analogs against Schistosoma japonicum . Bioorganic & Medicinal Chemistry Letters. 2016;26 (5):1386-1390 - 63.
Cowan N, Dätwyler P, Ernst B, Wang C, Vennerstrom JL, Spangenberg T, et al. Activities of N,N′-diarylurea MMV665852 analogs against Schistosoma mansoni . Antimicrobial Agents and Chemotherapy. 2015;59 (4):1935-1941 - 64.
Wu J, Wang C, Leas D, Vargas M, White KL, Shackleford DM, et al. Progress in antischistosomal N,N’-diaryl urea SAR. Bioorganic & Medicinal Chemistry Letters. 2018; 28 (3):244-248 - 65.
Probst A, Pujol E, Häberli C, Keiser J, Vazquez S. In vitro ,in vivo , and absorption, distribution, metabolism, and excretion evaluation of SF5-Containing N,N’-diarylureas as antischistosomal agents. Antimicrobial Agents and Chemotherapy. 2021;65 (10):e0061521 - 66.
Soto-Sánchez J, Ospina-Villa JD. Current status of quinoxaline and quinoxaline 1,4-di-N-oxides derivatives as potential antiparasitic agents. Chemical Biology & Drug Design. 2021; 98 (4):683-699 - 67.
Debbert SL, Hintz MJ, Bell CJ, Earl KR, Forsythe GE, Häberli C, et al. Activities of quinoxaline, nitroquinoxaline, and [1,2,4]triazolo[4,3-a]quinoxaline analogs of MMV007204 against Schistosoma mansoni . Antimicrobial Agents and Chemotherapy. 2021;65 (3):e01370-20. DOI: 10.1128/AAC.01370-20 - 68.
Padalino G, El-Sakkary N, Liu LJ, Liu C, Harte DSG, Barnes RE, et al. Anti-schistosomal activities of quinoxaline-containing compounds: From hit identification to lead optimisation. European Journal of Medicinal Chemistry. 2021; 226 :113823 - 69.
Pasche V, Laleu B, Keiser J. Screening a repurposing library, the Medicines for Malaria Venture Stasis Box, against Schistosoma mansoni . Parasites & Vectors 2018;11(1):1-8. - 70.
Uhl M, Aulwurm S, Wischhusen J, Weiler M, Ma JY, Almirez R, et al. SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro andin vivo . Cancer Research. 2004;64 (21):7954-7961 - 71.
Pasche V, Laleu B, Keiser J. Early antischistosomal leads identified from in vitro andin vivo screening of the Medicines for Malaria Venture Pathogen Box. ACS Infect Dis. 2019;5 (1):102-110 - 72.
Maccesi M, Aguiar PHN, Pasche V, Padilla M, Suzuki BM, Montefusco S, et al. Multi-center screening of the Pathogen Box collection for schistosomiasis drug discovery. Parasites & Vectors. 2019; 12 (1):493 - 73.
Zamanian M, Chan JD. High-content approaches to anthelmintic drug screening. Trends in Parasitology. 2021; 37 (9):780-789 - 74.
Biendl S, Häberli C, Keiser J. Discovery of novel antischistosomal scaffolds from the open access Pandemic Response Box. Expert Review of Anti-Infective Therapy. 2021:1-9 - 75.
Abdulla M, Ruelas DS, Wolff B, Snedecor J, Lim K, Xu F, et al. Drug discovery for schistosomiasis: Hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening. PLoS Neglected Tropical Diseases. 2009; 3 (7):e478 - 76.
Lago EM, Silva MP, Queiroz TG, Mazloum SF, Rodrigues VC, Carnauba PU, et al. Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasis. eBioMedicine. 2019; 43 :370-379 - 77.
Carvalho AA, Mafud AC, Pinto PL, Mascarenhas YP, de Moraes J. Schistosomicidal effect of the anti-inflammatory drug diclofenac and its structural correlation with praziquantel. International Journal of Antimicrobial Agents. 2014; 44 (4):372-374 - 78.
Neves BJ, Muratov E, Machado RB, Andrade CH, Cravo PVL. Modern approaches to accelerate discovery of new antischistosomal drugs. Expert Opinion on Drug Discovery. 2016; 11 (6):557-567 - 79.
Paveley RA, Mansour NR, Hallyburton I, Bleicher LS, Benn AE, Mikic I, et al. Whole organism high-content screening by label-free, image-based Bayesian classification for parasitic diseases. PLoS Neglected Tropical Diseases. 2012; 6 (7):e1762 - 80.
Mansour NR, Paveley R, Gardner JMF, Bell AS, Parkinson T, Bickle Q. High throughput screening identifies novel lead compounds with activity against larval, juvenile and adult Schistosoma mansoni . PLoS Neglected Tropical Diseases. 2016;10 (4):e0004659 - 81.
Simeonov A, Jadhav A, Sayed AA, Wang Y, Nelson ME, Thomas CJ, et al. Quantitative high-throughput screen identifies inhibitors of the Schistosoma mansoni redox cascade. PLoS Neglected Tropical Diseases. 2008;2 (1):e127 - 82.
Lea WA, Jadhav A, Rai G, Sayed AA, Cass CL, Inglese J, et al. A 1,536-well-based kinetic HTS assay for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase. Assay and Drug Development Technologies. 202;6 (4):551-555 - 83.
Gardner JMF, Mansour NR, Bell AS, Helmby H, Bickle Q. The discovery of a novel series of compounds with single-dose efficacy against juvenile and adult Schistosoma species. PLoS Neglected Tropical Diseases. 2021;15 (7):e0009490 - 84.
Lalli C, Guidi A, Gennari N, Altamura S, Bresciani A, Ruberti G. Development and validation of a luminescence-based, medium-throughput assay for drug screening in Schistosoma mansoni . PLoS Neglected Tropical Diseases. 2015;9 (1):e0003484 - 85.
Guidi A, Lalli C, Gimmelli R, Nizi E, Andreini M, Gennari N, et al. Discovery by organism based high-throughput screening of new multi-stage compounds affecting Schistosoma mansoni viability, egg formation and production. PLoS Neglected Tropical Diseases. 2017;11 (10):e0005994 - 86.
Guidi A, Lalli C, Perlas E, Bolasco G, Nibbio M, Monteagudo E, et al. Discovery and characterization of novel anti-schistosomal properties of the anti-anginal drug, perhexiline and its impact on Schistosoma mansoni male and female reproductive systems. PLoS Neglected Tropical Diseases. 2016;10 (8):e0004928 - 87.
Guidi A, Saraswati AP, Relitti N, Gimmelli R, Saccoccia F, Sirignano C, et al. ( )-(R)-and (−)-(S)-Perhexiline maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages. Bioorganic Chemistry. 2020;102 :104067 - 88.
Alger HM, Williams DL. The disulfide redox system of Schistosoma mansoni and the importance of a multifunctional enzyme, thioredoxin glutathione reductase. Molecular and Biochemical Parasitology. 2002;121 (1):129-139 - 89.
Kuntz AN, Davioud-Charvet E, Sayed AA, Califf LL, Dessolin J, Arnér ESJ, et al. Thioredoxin glutathione reductase from Schistosoma mansoni : An essential parasite enzyme and a key drug target. PLoS Medicine. 2007;4 (6):e206 - 90.
Song L, Li J, Xie S, Qian C, Wang J, Zhang W, et al. Thioredoxin glutathione reductase as a novel drug target: Evidence from Schistosoma japonicum . PLoS One. 2012;7 (2):e31456 - 91.
Perbandt M, Ndjonka D, Liebau E. Protective mechanisms of helminths against reactive oxygen species are highly promising drug targets. Current Medicinal Chemistry. 2014; 21 (15):1794-1808 - 92.
Angelucci F, Sayed AA, Williams DL, Boumis G, Brunori M, Dimastrogiovanni D, et al. Inhibition of Schistosoma mansoni thioredoxin-glutathione reductase by auranofin: Structural and kinetic aspects. The Journal of Biological Chemistry. 2009;284 (42):28977-28985 - 93.
Sayed AA, Simeonov A, Thomas CJ, Inglese J, Austin CP, Williams DL. Identification of oxadiazoles as new drug leads for the control of schistosomiasis. Nature Medicine. 2008; 14 (4):407-412 - 94.
Rai G, Sayed AA, Lea WA, Luecke HF, Chakrapani H, Prast-Nielsen S, et al. Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis. Journal of Medicinal Chemistry. 2009; 52 (20):6474-6483 - 95.
Song L, Luo H, Fan W, Wang G, Yin X, Shen S, et al. Oxadiazole-2-oxides may have other functional targets, in addition to SjTGR, through which they cause mortality in Schistosoma japonicum . Parasites & Vectors. 2016;9 (1):1-12 - 96.
Lyu H, Petukhov PA, Banta PR, Jadhav A, Lea WA, Cheng Q, et al. Characterization of lead compounds targeting the selenoprotein thioredoxin glutathione reductase for treatment of schistosomiasis. ACS infectious diseases. 2020; 6 (3):393-405 - 97.
Silvestri I, Lyu H, Fata F, Boumis G, Miele AE, Ardini M, et al. Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as “doorstop” for NADPH entry. ACS Chemical Biology. 2018; 13 (8):2190-2202 - 98.
Morel M, Vanderstraete M, Hahnel S, Grevelding CG, Dissous C. Receptor tyrosine kinases and schistosome reproduction: New targets for chemotherapy. Frontiers in Genetics. 2014; 5 :238 - 99.
Grevelding CG, Langner S, Dissous C. Kinases: Molecular stage directors for schistosome development and differentiation. Trends in Parasitology. 2018; 34 (3):246-260 - 100.
Wu K, Zhai X, Huang S, Jiang L, Yu Z, Huang J. Protein kinases: Potential drug targets against Schistosoma japonicum . Frontiers in Cellular and Infection Microbiology. 2021;11 :691757 - 101.
Cowan N, Keiser J. Repurposing of anticancer drugs: in vitro andin vivo activities againstSchistosoma mansoni . Parasites & Vectors. 2015;8 (1):1-9 - 102.
Kapp K, Knobloch J, Schüßler P, Sroka S, Lammers R, Kunz W, et al. The Schistosoma mansoni Src kinase TK3 is expressed in the gonads and likely involved in cytoskeletal organization. Molecular and Biochemical Parasitology. 2004;138 (2):171-182 - 103.
Levitzki A, Mishani E. Tyrphostins and other tyrosine kinase inhibitors. Annual Review of Biochemistry. 2006; 75 :93-109 - 104.
Hahnel S, Quack T, Parker-Manuel SJ, Lu Z, Vanderstraete M, Morel M, et al. Gonad RNA-specific qRT-PCR analyses identify genes with potential functions in schistosome reproduction such as SmFz1 and SmFGFRs. Frontiers in Genetics. 2014; 5 :170 - 105.
Vanderstraete M, Gouignard N, Cailliau K, Morel M, Lancelot J, Bodart J, et al. Dual targeting of insulin and venus kinase receptors of Schistosoma mansoni for novel anti-schistosome therapy. PLoS Neglected Tropical Diseases. 2013;7 (5):e2226 - 106.
Avelar LDGA, Gava SG, Neves RH, MCS S, Araújo N, Tavares NC, et al. Smp38 MAP kinase regulation in Schistosoma mansoni : Roles in survival, oviposition, and protection against oxidative stress. Frontiers in Immunology. 2019;10 :21 - 107.
Andrade LF, Mourao MM, Geraldo JA, Coelho FS, Silva LL, Neves RH, et al. Regulation of Schistosoma mansoni development and reproduction by the mitogen-activated protein kinase signaling pathway. PLoS Neglected Tropical Diseases. 2014;8 (6):e2949 - 108.
Long T, Neitz RJ, Beasley R, Kalyanaraman C, Suzuki BM, Jacobson MP, et al. Structure-bioactivity relationship for benzimidazole thiophene inhibitors of polo-like kinase 1 (PLK1), a potential drug target in Schistosoma mansoni . PLoS Neglected Tropical Diseases. 2016;10 (1):e0004356 - 109.
Buro C, Beckmann S, Oliveira KC, Dissous C, Cailliau K, Marhöfer RJ, et al. Imatinib treatment causes substantial transcriptional changes in adult Schistosoma mansoni in vitro exhibiting pleiotropic effects. PLoS Neglected Tropical Diseases. 2014;8 (6):e2923 - 110.
Wang J, Paz C, Padalino G, Coghlan A, Lu Z, Gradinaru I, et al. Large-scale RNAi screening uncovers therapeutic targets in the parasite Schistosoma mansoni . Science. 2020;369 (6511):1649-1653 - 111.
Oliveira MF, d’Avila JC, Torres CR, Oliveira PL, Tempone AJ, Rumjanek FD, et al. Haemozoin in Schistosoma mansoni . Molecular and Biochemical Parasitology. 2000;111 (1):217-221 - 112.
Xiao S, Sun J. Schistosoma hemozoin and its possible roles. International Journal for Parasitology. 2017;47 (4):171-183 - 113.
Correa Soares JB, Menezes D, Vannier-Santos MA, Ferreira-Pereira A, Almeida GT, Venancio TM, et al. Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols. PLoS Neglected Tropical Diseases. 2009; 3 (7):e477 - 114.
De Villiers KA, Egan TJ. Recent advances in the discovery of haem-targeting drugs for malaria and schistosomiasis. Molecules. 2009; 14 (8):2868-2887 - 115.
Sun J, Li C, Wang S. Organism-like formation of Schistosoma hemozoin and its function suggest a mechanism for anti-malarial action of artemisinin. Scientific Reports. 2016;6 (1):1-10 - 116.
Okombo J, Singh K, Mayoka G, Ndubi F, Barnard L, Njogu PM, et al. Antischistosomal activity of pyrido[1,2-a]benzimidazole derivatives and correlation with inhibition of beta-hematin formation. ACS Infect Dis. 2017; 3 (6):411-420 - 117.
Mayoka G, Keiser J, Häberli C, Chibale K. Structure-activity relationship and in vitro absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies of N-aryl-3-trifluoromethyl pyrido[1,2-a]benzimidazoles that are efficacious in a mouse model of schistosomiasis. ACS Infectious Diseases. 2019;5 (3):418-429 - 118.
Probst A, Chisanga K, Dziwornu GA, Haeberli C, Keiser J, Chibale K. Expanding the activity profile of pyrido[1,2-a]benzimidazoles: Synthesis and evaluation of novel N1-1-phenylethanamine derivatives against Schistosoma mansoni . ACS Infectious Diseases. 2021;7 (5):1032-1043 - 119.
McKerrow JH. Development of cysteine protease inhibitors as chemotherapy for parasitic diseases: Insights on safety, target validation, and mechanism of action. International Journal for Parasitology. 1999; 29 (6):833-837 - 120.
Sajid M, McKerrow JH. Cysteine proteases of parasitic organisms. Molecular and Biochemical Parasitology. 2002; 120 (1):1-21 - 121.
Fonseca NC, da Cruz LF, da Silva VF, do Nascimento Pereira GA, de Siqueira-Neto JL, Kellar D, et al. Synthesis of a sugar-based thiosemicarbazone series and structure-activity relationship versus the parasite cysteine proteases rhodesain, cruzain, and Schistosoma mansoni cathepsin B1. Antimicrobial Agents and Chemotherapy. 2015;59 (5):2666-2677 - 122.
Abdulla M, Lim K, Sajid M, McKerrow JH, Caffrey CR. Schistosomiasis mansoni : Novel chemotherapy using a cysteine protease inhibitor. PLoS Medicine. 2007;4 (1):e14 - 123.
Jilkova A, Rezacova P, Lepsik M, Horn M, Vachova J, Fanfrlik J, et al. Structural basis for inhibition of cathepsin B drug target from the human blood fluke, Schistosoma mansoni . Journal of Biological Chemistry. 2011;286 (41):35770-35781 - 124.
Fennell B, Naughton J, Barlow J, Brennan G, Fairweather I, Hoey E, et al. Microtubules as antiparasitic drug targets. Expert Opinion on Drug Discovery. 2008; 3 (5):501-518 - 125.
Chatterji BP, Jindal B, Srivastava S, Panda D. Microtubules as antifungal and antiparasitic drug targets. Expert Opinion on Therapeutic Patents. 2011; 21 (2):167-186 - 126.
Bogitsh BJ. Schistosoma mansoni : Colchicine and vinblastine effects on schistosomule digestive tract developmentin vitro . Experimental Parasitology. 1977;43 (1):180-188 - 127.
Monti L, Cornec AS, Oukoloff K, Kovalevich J, Prijs K, Alle T, et al. Congeners derived from microtubule-active phenylpyrimidines produce a potent and long-lasting paralysis of Schistosoma mansoni in vitro . ACS Infectious Diseases. 2021;7 (5):1089-1103 - 128.
Monneret C. Histone deacetylase inhibitors for epigenetic therapy of cancer. Anti-Cancer Drugs. 2007; 18 (4):363-370 - 129.
Dubois F, Caby S, Oger F, Cosseau C, Capron M, Grunau C, et al. Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni . Molecular and Biochemical Parasitology. 2009;168 (1):7-15 - 130.
Oger F, Dubois F, Caby S, Noel C, Cornette J, Bertin B, et al. The class I histone deacetylases of the platyhelminth parasite Schistosoma mansoni . Biochemical and Biophysical Research Communications. 2008;377 (4):1079-1084 - 131.
Pierce J, Dubois-Abdesselem F, Lancelot J, Andrade L, Oliveira G. Targeting schistosome histone modifying enzymes for drug development. Current Pharmaceutical Design. 2012; 18 (24):3567-3578 - 132.
Marek M, Kannan S, Hauser AT, Moraes Mourao M, Caby S, Cura V, et al. Structural basis for the inhibition of histone deacetylase 8 (HDAC8), a key epigenetic player in the blood fluke Schistosoma mansoni . PLoS Pathogens. 2013;9 (9):e1003645 - 133.
Heimburg T, Chakrabarti A, Lancelot J, Marek M, Melesina J, Hauser AT, et al. Structure-based design and synthesis of novel inhibitors targeting HDAC8 from Schistosoma mansoni for the treatment of schistosomiasis. Journal of Medicinal Chemistry. 2016;59 (6):2423-2435 - 134.
Ghazy E, Heimburg T, Lancelot J, Zeyen P, Schmidtkunz K, Truhn A, et al. Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis. European Journal of Medicinal Chemistry. 2021; 225 :113745 - 135.
Kalinin DV, Jana SK, Pfafenrot M, Chakrabarti A, Melesina J, Shaik TB, et al. Structure-based design, synthesis, and biological evaluation of triazole-based smHDAC8 inhibitors. ChemMedChem. 2020; 15 (7):571-584 - 136.
Vogerl K, Ong N, Senger J, Herp D, Schmidtkunz K, Marek M, et al. Synthesis and biological investigation of phenothiazine-based benzhydroxamic acids as selective histone deacetylase 6 inhibitors. Journal of Medicinal Chemistry. 2019; 62 (3):1138-1166 - 137.
Pereira AS, Amaral MS, Vasconcelos EJ, Pires DS, Asif H, da Silva LF, et al. Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni in vitro by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolism. PLoS Neglected Tropical Diseases. 2018;12 (10):e0006873 - 138.
Lancelot J, Caby S, Dubois-Abdesselem F, Vanderstraete M, Trolet J, Oliveira G, et al. Schistosoma mansoni sirtuins: Characterization and potential as chemotherapeutic targets. PLoS Neglected Tropical Diseases. 2013;7 (9):e2428 - 139.
Monaldi D, Rotili D, Lancelot J, Marek M, Wossner N, Lucidi A, et al. Structure-reactivity relationships on substrates and inhibitors of the lysine deacylase sirtuin 2 from Schistosoma mansoni (SmSirt2). Journal of Medicinal Chemistry. 2019;62 (19):8733-8759 - 140.
Long T, Rojo-Arreola L, Shi D, El-Sakkary N, Jarnagin K, Rock F, et al. Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target. PLoS Neglected Tropical Diseases. 2017; 11 (7):e0005680 - 141.
Botros SS, William S, Sabra AA, El-Lakkany NM, Seif El-Din SH, Garcia-Rubia A, et al. Screening of a PDE-focused library identifies imidazoles with in vitro andin vivo antischistosomal activity. International Journal for Parasitology: Drugs and Drug Resistance. 2019;9 :35-43 - 142.
Sebastián-Pérez V, Schroeder S, Munday JC, Van Der Meer T, Zaldívar-Díez J, Siderius M, et al. Discovery of novel Schistosoma mansoni PDE4A inhibitors as potential agents against schistosomiasis. Future Medicinal Chemistry. 2019;11 (14):1703-1720 - 143.
Calil FA, David JS, Chiappetta ER, Fumagalli F, Mello RB, Leite FH, et al. Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase. European Journal of Medicinal Chemistry. 2019;167 :357-366 - 144.
Chen G, Foster L, Bennett JL. Antischistosomal action of mevinolin: Evidence that 3-hydroxy-methylglutaryl coenzyme A reductase activity in Schistosoma mansoni is vital for parasite survival. Naunyn-Schmiedeberg’s Archives of Pharmacology. 1990;342 (4):477-482 - 145.
Rojo-Arreola L, Long T, Asarnow D, Suzuki BM, Singh R, Caffrey CR. Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis. PLoS One. 2014; 9 (1):e87594 - 146.
Probst A, Nguyen TN, El-Sakkary N, Skinner D, Suzuki BM, Buckner FS, et al. Bioactivity of farnesyltransferase inhibitors against Entamoeba histolytica andSchistosoma mansoni . Frontiers in Cellular and Infection Microbiology. 2019;9 :180 - 147.
Da’dara AA, Angeli A, Ferraroni M, Supuran CT, Skelly PJ. Crystal structure and chemical inhibition of essential schistosome host-interactive virulence factor carbonic anhydrase SmCA. Common Biology. 2019; 2 (1):1-11 - 148.
Jacques SA, Kuhn I, Koniev O, Schuber F, Lund FE, Wagner A, et al. Discovery of potent inhibitors of Schistosoma mansoni NAD catabolizing enzyme. Journal of Medicinal Chemistry. 2015;58 (8):3582-3592 - 149.
Ziniel PD, Karumudi B, Barnard AH, Fisher EM, Thatcher GR, Podust LM, et al. The Schistosoma mansoni Cytochrome P450 (CYP3050A1) is essential for worm survival and egg development. PLoS Neglected Tropical Diseases. 2015;9 (12):e0004279 - 150.
Mader P, Blohm AS, Quack T, Lange-Grunweller K, Grunweller A, Hartmann RK, et al. Biarylalkyl carboxylic acid derivatives as novel antischistosomal agents. ChemMedChem. 2016; 11 (13):1459-1468 - 151.
Blohm AS, Mäder P, Quack T, Lu Z, Hahnel S, Schlitzer M, et al. Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro . Parasitology Research. 2016;115 (10):3831-3842