Dr.Riscoe?sExperimentalChemotherapylaboratoryfocusesonthediscovery,optimizationandtranslational development of antiparasitic drugs, especially drugs for treatment and prevention of malaria, a severe and potentially fatal tropical disease. Using modern methods of drug design and chemical synthesis his laboratory hassuccessfullycreated5novelantimalarial?chemotypes?withexemplarymoleculesineachcategorythatare orallybioavailableandcurativeinmousemodelsofinfection.ThePortlandVAandneighboringOHSUhavefiled for patent protection on all 5 chemotypes which include: 1)Dual functional acridones with blood stage activity that interact synergistically with many standard antimalarial agents, 2) 4-Aminoquinoline derivatives (?Pharmachins?), designed to replace chloroquine, that are rapidly active against multidrug resistant strains of Plasmodium falciparum parasites, 3) Quinolones (i.e., ELQ-300) that block parasite mitochondrial respiration andactvs.theblood,liver,gametocyte,andvectorstagesofparasitedevelopment,4)ProdrugsofELQ-300for improved oral delivery and for injectable sustained-release and long-term protection against malaria, and 5) Biguanideswithenhancedsynergyincombinationwithanti-respiratoryantimalarialdrugssuchasatovaquone andELQ-300. It is noteworthy that ELQs (e.g., ELQ-316) are also potent against other parasites including Toxoplasma gondiiandBabesiamicrotiwithprovenactivitydemonstratedinvitroaswellasinvivo.T.gondiiisaeukaryotic intracellular parasite estimated to have infected billions of people worldwide, placing them at risk for toxoplasmosis. Fetuses and immune-compromised persons (e.g., HIV patients, transplant patients, and individuals undergoing cancer chemotherapy) are susceptible to severe toxoplasmosis, which can be fatal or leadtopermanentocularorneurologicdisability.Evenhealthypeoplewithoutimmunodeficiencyaresusceptible tooculardiseasewhichmaycausevisionloss.B.microticausesbabesiosiswhichistransmittedbyticks.Itis endemicintheNewEnglandregionoftheUnitedStateswhereitiscalled,?NantucketFever?.Likemalariaand toxoplasmosis,babesiosisisapotentiallyfatalinfectionandnewandeffectivedrugsareurgentlyneeded.Itis noteworthy that B. microti is a common co-infection associated with Lyme disease and is regarded as the foremostinfectiousrisktotheU.S.bloodsupply. ThePortlandVA?sExperimentalChemotherapyLabalsoinvestigatesdrugmechanismofactionbyuseof methods that are traditional to the fields of biochemistry, chemical biology and molecular parasitology. Dr. Riscoe?slaboratoryreceivessupportfromtheDepartmentofVeteransAffairs,NationalInstitutesofHealth,and the Medicines for Malaria Venture and he maintains an active collaboration with members of the Division of ExperimentalTherapeuticsattheWalterReedArmyInstituteforResearch.Hecontinuestoserveasaninvited reviewer for the US DOD?sPeer Reviewed Medical Research Program (PRMRP) and the NIH. The long-term objective of Dr. Riscoe?s malaria research is to develop drugs that are inexpensive, safe and effective in prevention and treatment of the most vulnerable populations, young children and pregnant women, and ultimatelytodevelopacocktailofdrugsthatmaybeusedtoeradicatethedisease.
U.S. servicemen and women encountered malaria during the Revolutionary War and every US warsincethattime.Malariaandantimalarialsaretwoofthemostcommonbiologicalandchemical exposures of US veterans. Multidrug resistant parasites have spread to virtually all malarious regions of the world. New drug strategies for prevention and treatment of malaria are urgently needed.Mylabiscommittedtothedevelopmentofsafeandeffectivedrugsthatcanbeusedin all individuals, regardless of their station: children, adults, men, women, pregnant, unborn, or geneticallydeficientintheenzymeglucose6-phosphatedehydrogenase(G6PD).Theresultant advantages of avoiding drug toxicity, febrile illness and complex medical management during deploymentareself-evident,asarethebenefitstobothshortandlong-termhealthofthesoldier.
