SummaryThere is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. We describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the parasite, with good pharmacokinetic properties, and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapsein a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.
CRISPR-Cas9
is a genome editing technology with major impact in
life sciences. In this system, the endonuclease Cas9 generates double
strand breaks in DNA upon RNA-guided recognition of a complementary
DNA sequence, which strictly requires the presence of a protospacer
adjacent motif (PAM) next to the target site. Although PAM recognition
is essential for cleavage, it is unknown whether and how PAM binding
activates Cas9 for DNA cleavage at spatially distant sites. Here,
we find evidence of a PAM-induced allosteric mechanism revealed by
microsecond molecular dynamics simulations. PAM acts as an allosteric
effector and triggers the interdependent conformational dynamics of
the Cas9 catalytic domains (HNH and RuvC), responsible for concerted
cleavage of the two DNA strands. Targeting such an allosteric mechanism
should enable control of CRISPR-Cas9 functionality.
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