Malaria

characterisation of malaria

fever, damage of internal organs and brain

either by Plasmodium falciparum (most mortality) or Plasmodium vivax (most morbidity)

malaria treatments

insecticides and bednets (insecticide resistance)

antimalarial drugs e.g. chloroquine (rapid resistance)

RTS,S/AS01 vaccine

effective chemotherapies

P. falciparum life cycle

infection, then sporozoites enter liver and undergo prolific replication

leads to merozoites which enter RBCs (disease state) (drugs target this)

they undergo asexual replication every 48 hours

enter sexual forms, gametocytogenesis which are transmitted to mosquito and form zygote

causes anaemia and shortness of breath

problems vaccines face

complex life cycle

can evade immune system

antigenic variation of surface proteins and switching of var genes

Fansidar

contains sulphadoxine and pyrimethamine

kills parasite and cures disease

inhibits dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR) required for DNA synthesis

role of dihydropteroate synthetase (DHPS)

joins DHPP and PABA to give 7,8 dihydropteroate and PPi

role of Sulfadoxine

competitive inhibitor of PABA binding to DHPS (enzyme) by mimicking PABA

role of dihydrofolate reductase (DHFR)

converts a C=C double bond to a C-C single bond

reducing dihydrofolate to tetrahydrofolate and NADP+

(NADP-H bond breaks and H adds into double bond)

role of Pyrimethamine

mimics part of dihydrofolate (DHF)

cheap and simple

mutation against pyrimethamine

Ser108Asn mutation

Asn has more bulk than Ser, so pyr can’t bind but enz function not affected

mutation affects pyr potency, so much more is needed to inhibit enzyme

WR99210 against pyr resistance

similar structure to pyr with a long chain between the rings which can swing away from Ser/Asp108

WR99210 is much less affected by mutations and is a good inhibitor as it binds in a conformation not affected by pyr resistant mutations

low bioavailability

p218 against pyr resistance

occupies almost the same space as DHF

goodness of fit to substrate envelope