alsotoextracellularglidingandcell inva-sion. Monitoring how and where these filamentsemerge,elongate, andrecycle willcertainlyrequirefutureimaging adjust-ments to increase signal sensitivity, speed, and resolution. Thanks to the great achievement in generating a tool that all the community was waiting for, and in conjunction with photoactivation andinactivation-basedapproaches,and super-resolution live-cell imaging, the mystery of the actin contribution to the lyticcycleoftachyzoitesmightbefinally elucidatedinthenearfuture.
Periz et al. [7] now describe unique F-actin networks that (1) connect one daughter to the other, and presumably contribute to the rosette pattern while allowing interparasite communication, and(2)collapsewhileF-actinretreatsto theRBbeforethenetworksreformagain and expand throughout the PV. Break-down of the network also precedes tachyzoite egress from the PV and the host cell while residual F actin can still beseenwithintheRB(Figure1). 1InstituteofAdvancedBioSciences,InstitutNationaldela SantéetdelaRechercheMédicaleU1209,Centre NationaldelaRechercheScientifiqueUMR5309, UniversitéGrenobleAlpes,38000,Grenoble,France
*Correspondence:isabelle.tardieux@inserm.fr(I.Tardieux).
http://dx.doi.org/10.1016/j.pt.2017.06.007
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142,1879–1884
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15, 1
Forum
The
Future
of
Drug
Development
for
Neglected
Tropical
Diseases:
How
the
European
Commission
Can
Continue
to
Make
a
Difference
Raymond
J.
Pierce,
1,*
Jane
MacDougall,
2,*
Rob
Leurs,
3,* and
Maria
Paola
Costi
4,*
Inthisarticle,thefourcoordinators
of neglected tropical disease
(NTD) drug development projects
funded undertheEuropean
Com-mission (EC) Framework
Pro-gramme 7 argue that the EC
should reassess their funding
strategytocoverthesteps
neces-sarytotranslatealeadcompound
intoadrugcandidatefortestingin clinicaltrials,andsuggestwaysin
whichthismightbeachieved.
ECFundingofNTDDrug Development
TheEChasconsistentlyandsubstantially supported research into NTDs, starting well before the London Declaration of 2012 (http://unitingtocombatntds.org/ resource/london-declaration), which put thecontroloreliminationofNTDsatthe forefrontofglobaleffortsto‘chartanew
course toward health and sustainability amongtheworld’spoorestcommunities toastronger,healthierfuture’.However, grantsforresearchonNTDsrepresented only11%ofthetotalfundingforinfectious diseases during the EC Framework Programmes (FP) 5 to 7 up to 2013, 70% going to the so-called‘Big Three’ diseases: malaria, tuberculosis, and HIV/AIDS [1]. The development of new drugs is particularly important in order to circumvent problems with current treatments, including drug resistance, severe side-effects, or exacting dosing schedules. There is a recognized need to identify new chemical entities(NCEs) as candidate drugs in order to both improve patient care and meet targets for elimination, particularly of neglected parasiticdiseases[2].Nevertheless,only 6% oftheECinfectiousdiseasefunding wasdedicatedtodrugdevelopment.
ECFP7 DrugDiscoveryProjects The EC has beennotably successful in bringing together large, multinational researchnetworks.Foursuchconsortia, with the acronyms NMTrypI (http://
fp7-nmtrypi.eu), KINDReD (http://
kindred-fp7.com/), A-ParaDDisE (http:// a-paraddise.cebio.org/), and PDE4NPD (www.pde4npd.eu),involving morethan 50teamsinEurope,Africa,India,South America, Australia, and the USA, were fundedinthelastcallunderFP7related to drugdevelopmentinneglected infec-tiousdiseases.Theprojectstargetedthe major chronic parasitic diseases leish-maniasis,Chagasdisease,sleeping sick-ness, schistosomiasis, and malaria. Together, these diseases affect more than a billion people worldwide, cause hundreds of thousands of deaths, and aremajorcontributorstothepovertytrap inthecountriesconcerned[2].The proj-ectsweregiventhefollowingobjectives:
Toestablishacommondrug-discovery platformthatshouldhavethecapacity to undertake screening of compound libraries,leaddevelopment.
Totestvalidatedhitcompoundsin rel-evant animal models as well as
toxicology and safety testing of new drugcandidates.
Thefourprojectspursueddistinct strate-gies for drug discovery, involving both phenotypic screening, target-based methods, and repurposing of existing approveddrugs,andhaveallmade sig-nificant progress. Based on the criteria fortheselectionof‘hit’ and‘lead’ com-pounds, recently defined [3], well over 100 hits have been identified of which morethan 10 can so farbedefined as leadcompounds withpromisingprofiles inanimalstudiesandsignificantpotential forfurtherdevelopment.Thesenumbers will growas the projects reach term. In addition, novel drug targets have been identified and validated for each of the parasites studied, homology models andcrystalstructuresoftargetenzymes have been resolved, andnew chemical entities identified as potential drugs of interest both in NTDs and other pathologies.
Importantly,as suggested bythe EC at the time of funding, the four consortia
have worked in close collaboration throughout the course of their projects undertheumbrellaofcommon‘Synergy’ activities.Theseinvolvedregular discus-sions,ajointsymposium in2016, com-mon partner teams and/or external advisoryboardmembers,resource pool-ing,andacommondatastorageplatform (https://fp7h-synergy.h-its.org/).Thishas enabledthemtoadoptacommon strat-egytofacethechallengeofensuringthat theadvancesmadewillnotbelostonce thecurrentprojectscometoanend. Cru-cially,supportisneededfordevelopinghit andleadcompoundsfrominvivoanimal studies through preclinical testing up to and including phase I clinical trials. This involves rigorous pharmacokinetic, pharmacodynamic, and toxicity studies (Absorption, Distribution, Metabolism, Excretion, and Toxicity; ADMET) and drugproductionaccordingtoGood Lab-oratory Practice/Good Manufacturing Practice(GLP/GMP)standards(Figure1). Nofunding opportunities exist for these typesofstudyinthecurrentECresearch programme, Horizon2020 (H2020),
which at present supports only clinical trialsthroughtheEuropean&Developing Countries Clinical Trials Partnership (EDCTP).While NTDshavebeen added to the remit ofthe EDCTP, the support proposed in the business plan until 2024 (http://www.edctp.org/web/app/ uploads/2016/12/EDCTP-Strategic-Business-Plan-2014-2024.pdf)is restric-tive, whetherfordiagnostics, vaccineor drugdevelopment.Supportforthelatter concernspredominantlyphaseIItophase IIIclinicaltrials,withafocusondrug com-binations,andonlyinsub-SaharanAfrica (rulingoutsupportforclinicaltrialsonsome important NTDs like Chagas disease). Moreover, only in the case of diseases wheretreatmentsare‘inadequateor lack-ing’willphaseItrialsbefunded.Thisleaves a yawning‘fundinggap’between hit-to-leaddevelopmentandclinicaltrials.
FundingInitiativesforNTDDrug Development
Mechanisms do exist to fill the funding gapandtakevalidatedleadcompounds throughthecomplexandcostly early-clin-ical phase of testing. These are mainly nonprofit initiatives funded by various sources, including, for example,the Bill &MelindaGatesfoundation(http://www. gatesfoundation.org/),governments,and the pharmaceutical industry. Examples aretheDrugsforNeglectedDiseases Ini-tiative (DNDi; http://www.dndi.org/), WIPO Re:search (http://www.wipo.int/ research/en/), and the Medicines for Malaria Venture (https://www.mmv.org/
). The DNDi hasoverseen the progress offexinidazoletophaseIIb/IIIclinicaltrials for the treatment of human African try-panosomiasis,to phaseIIaforthe treat-mentofChagasdisease,andtophaseIIa in combination with miltefosine for the treatmentofleishmaniasis,andhasother leadsinthepipelineforNTDs,aswellas forotherdiseasessuchaspaediatricHIV andhepatitisC.Nevertheless,duetothe highattritionrateforcandidatedrugsatall stages ofthedevelopmentpipeline,it is advantageous to have morecandidates to feed into it. This again implies Drug repurposing Phenotypic screening Target-based screening Target
idenficaon HIT LEAD
Candidate (preclinical studies) Candidate (clinical studies) DRUG Synthesis PK studies Toxicological studies Crystallography and molecular modeling In vitro acvity
Figure1.TheDrugDiscoveryPipeline.
appropriatefunding:apooledR&Dfund hasbeenproposedbytheWHO[4]but thisremainstheoretical.Theabsenceof suchalargepooledfundingmechanism andthe fragmentation ofcurrent efforts aretobedeplored[2,5].
HowtheECCanMakea Difference
Theconsiderablecontributionofthe EC-fundedprogrammesto NTDresearchis not in question. It is also clear that emphasis has previously been placed onbasic research,but that this should nowshiftinordertoaddressthegapsin the pipelines for the development of drugs, vaccines, and diagnostics. The most obvious gap separates drug hit andlead developmentfrom thetype of clinicaltrial fundedby the EDCTP.The next logical step for the drug develop-ment investment strategy of the EU would be to fund a call within H2020, tobuilduponthe synergy developedin thelastFP7call.Thiswouldenable con-tinued interaction between academia andsmallandmedium-sizedenterprises bycreatingaplatformtotakeonthetask of bridging the gap between lead opti-mization and early-stage clinical trials (phases I–II). Lead compounds devel-opedbythefourconsortia,butalsofrom other sources (e.g., teamsparticipating in the current EC-funded COST 1307 initiative)wouldfeedtheplatform regard-less of the parasitic disease targeted, overcoming the problem of fragmenta-tion amongst groups in the field and removingreplicationofeffort.Whilethis should not replace funding of basic research, it would lead to an increase inthe density ofthe different stagesof preclinical testing and in the numbers of candidates entering phase I clinical trials.Inthiswaythepreviousinvestment in NTD drug discovery would be consolidated.
Whileitisevidentthatnosinglefundercan completelycoverthe whole drug devel-opment pipeline, targeted funding, as suggested here, could attract support
from other sources, including industry, foundations,andnongovernmental orga-nizations, and collaborations between these stakeholders should be sought. Finally, the cooperation of the pharma-ceutical industry, whose expertise is essential for any drug to finally reach the clinic, could beengineered through the Innovative Medicines Initiative (IMI), cofundedbytheECandindustry,by add-ing NTD drug development to the IMI remit.
Acknowledgments
Theauthorsacknowledgefundingunderthe Euro-peanUnion’sSeventhFrameworkprogrammeforthe projectsA-ParaDDisEhttp://a-paraddise.cebio.org/
(grant agreement number: 602080), KINDReD (grantagreementnumber:602773),NMTrypI(grant agreementnumber:603240)andPDE4NPD(grant agreementnumber:602666).
1Univ.Lille,CNRS,Inserm,CHULille,InstitutPasteurde Lille,U1019–UMR8204–CIIL–Centred'Infectionet d'ImmunitédeLille,F-59000Lille,France
2Photeomix,IPResearchConsultingSAS,NoisyleGrand, 93160,France
3AmsterdamInstituteforMolecules,Medicinesand Systems(AIMMS),DivisionofMedicinalChemistry, FacultyofScience,VrijeUniversiteitAmsterdam,De Boelelaan1108,1081HZAmsterdam,TheNetherlands 4DepartmentofLifeSciences,UniversityofModenaand ReggioEmilia,ViaG.Campi103,41125Modena,Italy
*Correspondence: raymond.pierce@pasteur-lille.fr(R.J.Pierce), jmacdougall@photeomix.com(J.MacDougall), r.leurs@vu.nl(R.Leurs), mariapaola.costi@unimore.it(M.P.Costi). http://dx.doi.org/10.1016/j.pt.2017.04.007 References
1.Cochrane,G.etal.(2017)EvaluationoftheImpactofthe EuropeanUnion’sResearchFundingforPovertyRelated andNeglectedDiseases.FinalReport.Preparedfor Euro-peanCommission,DirectorateGeneralforResearchand Innovation(inpress)
2.Hotez, P. et al. (2016) Eliminating the neglected tropical
diseases: translational science and new technologies. PLoS
Negl. Trop. Dis. 10, e0003895
3.Katsuno, K. et al. (2015) Hit and lead criteria in drug
discov-ery for infectious diseases of the developing world. Nat. Rev.
Drug Discov. 14, 751–758
4.WHO(2012)ResearchandDevelopmenttoMeetHealth Needs in Developing Countries: Strengthening Global FinancingandCoordination.ReportoftheConsultative ExpertWorkingGroup onResearchandDevelopment: FinancingandCoordinationGenevahttp://www.who.int/ phi/CEWG_Report_5_April_2012.pdf?ua=1
5.Balasegaram, M. et al. (2015) A global biomedical R&D fund
andmechanismforinnovationsofpublichealthimportance.
PLoSMed.12,e1001831
Forum
Insights
on
Heme
Synthesis
in
the
Malaria
Parasite
Viswanathan
A.
Nagaraj
1,*
and
Govindarajan
Padmanaban
2,*
The malaria parasite has a
func-tionalheme-biosyntheticpathway,
althoughitcanaccesshost
hemo-globin-heme.Thehemepathwayis
dispensablefor bloodstages,but
essential in the mosquito stages
which do not acquire
hemoglo-bin-heme. We propose that the
blood stage parasites maintain a
dynamichemepoolthrough
multi-pleback-up mechanisms.
Heme PathwayintheMalaria Parasite
Heme-containing cytochromes are essential forthe functioningof the elec-trontransportchain(ETC) inthemalaria parasite.TheETCisrequiredtosupport pyrimidine biosynthesis in the blood stages, whereas in the sexualand liver stagesit isalso involvedinATP genera-tion and oxidative metabolism. The malaria parasiteacquireshost hemoglo-bin inthebloodstagesanddigestsit in thefoodvacuoletogenerateaminoacids. Sinceaccumulationoffreehemeistoxic, it storesthe excess heme derived from hemoglobinashemozoinpigment,a bio-crystallizedformofheme-aggregates[1]. Interestingly,theparasitecansynthesize itsownhemefromglycine,andtheentire pathwayinvolvesthreedifferentparasite compartments:mitochondria,apicoplast, andcytosol (Figure1A)[2].Studieswith Plasmodium berghei-infected mice [3]
and Plasmodium falciparum in cultures
[4]usingknockout(KO)parasites gener-atedford-aminolevulinicacidsynthetase (ALAS) and ferrochelatase (FC),the first and last enzymes of heme-biosynthetic
