Chemistry Reference
In-Depth Information
the.folded.structure.may.be.extremely.stable.and.structurally.different.than.the.wild-
type..Thus,.to.understand.the.monomer.and.early.aggregation.mechanism,.proteins.
should.remain.in.solution.at.all.times.
The.early.aggregation.and.monomer.hypothesis.is.currently.being.tested.in.the.
case.of.another.closely.related.neurodegenerative.disease,.Alzheimer's.Eli.Lilly.has.
developed.a.drug.called.Solunezumab.that.is.presently.in.Phase.III.clinical.trials,.
and.is.one.of.the.few.Alzheimer's.drugs.that.has.successfully.continued.on.to.this.
phase. of. clinical. trials.
8
. This. drug. has. an. interesting. mechanism. when. compared.
to. other. Alzheimer's. drugs. that. are. being. developed. and/or. tested.. Most. other.
Alzheimer's.drugs.work.by.inhibiting.enzymes.that.are.responsible.for.cleaving.the.
amyloid. protein. into. the. amyloid-β. state.
70
. The. new. drug. is. actually. a. monoclo-
nal.antibody.that.speciically.binds.only.to.the.mid-domain.of.the.monomeric.form.
of. the. amyloid-β. protein. that. is. believed. to. play. a. pathogenic. role. in. the. progres-
sion.of.Alzheimer's.disease.through.its.overproduction.and.subsequent.aggregation.
into.amyloid.plaques.
10
.The.antibody.then.causes.the.bound.protein.to.be.relocated.
outside. of. the. neurons. into. the. cerebral. spinal. luid. and. blood. plasma,. effectively.
reducing. the. amyloid-β. concentration. in. the. brain.
9
. By. selectively. binding. to. the.
monomer.and.reducing.its.concentration,.the.drug.effectively.prevents.aggregation..
If.Solunezumab.successfully.completes.Phase.III.clinical.trials,.then.it.could.poten-
tially.change.the.approach.of.treatment.development.for.diseases.resulting.from.pro-
tein.aggregation.
Similar.to.drug.studies.regarding.Alzheimer's.disease,.information.gained.about.
the.structure.and.conformation.of.synuclein.monomers.in.solution,.their.solubility,.
and.how.they.dimerize.in.solution.(reaction.mechanism).could.help.to.design.more.
eficient.drugs.that.increase.the.solubility.of.these.monomers.and.prevent.oligomer-
ization.via.blocking.pathways.to.oligomerization.of.these.proteins..Our.studies.are.
directly.linked.to.these.properties.and.we.provide.detailed.insights.into.the.hydration.
characteristics.of.these.monomers,.which.in.turn.are.directly.related.to.their.behav-
ior.in.solution.and.solubility..The.structural.and.thermodynamic.properties.that.we.
report. herein. may. be. used. in. the. design. of. more. effective. drugs. or. treatments. for.
Parkinson's.disease.
Additionally,. the. RDFs. of. the. backbone. carboxyl. carbon. and. nitrogen. of. resi-
dues.1,.53,.and.140.were.calculated.via.MD.simulations.in.aqueous.solution.and.are.
shown.in.Figure.2.5..By.looking.at.the.atomic.RDFs.for.these.speciic.residues,.the.
differences.in.hydration.can.be.more.accurately.determined.and.attributed.to.spe-
ciic.amino.acids..For.residue.1,.both.variants.equilibrate.to.very.similar.minima.
and.irst.shell.coordination.numbers.in.both.the.C.and.N.residues..In.the.case.of.
residue. 53,. however,. the. irst. minimum. (irst. shell). occurs. at. a. shorter. distance.
and.a.much.lower.value.for.the.mutant.than.in.the.case.of.the.wild-type.synuclein..
The.result.of.this.mutation.makes.the.protein.much.more.hydrophobic.in.this.area.
of. the. protein. than. the. wild-type.. Also,. the. carboxyl. side. of. the. amino. acid. is.
more. hydrated. than. the. amine. terminus.. The. hydroxyl. group. on. the. side. of. the.
threonine. amino. acid. is. hydrogen. bonded. to. another. residue. on. the. N-terminal.
side. so. the dehydration. of. the. amine. terminus. from. the. wild. to. mutant. type. is.
expected..For.residue.140,.the.RDFs.show.that.the.majority.of.the.coordination.at.
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