Abstract The malaria parasite Plasmodium falciparum is responsible for an estimated 200 million cases of disease and nearly 500,000 deaths annually, while Plasmodium vivax infects another 70-390 million people annually and is associated with relapsing infection. While antimalarial drug discovery has seen increased attention in recent years, a serious threat is posed by multi-drug resistant parasites, and particularly the artemisinin-resistant, K13 mutant strains observed clinically in Southeast Asia. Our long-term objective is to develop new antimalarial agents that target translation repression in Plasmodium parasites to counter these emerging threats. In Plasmodium parasites, as in higher eukaryotes, translation repression is conferred by the phosphorylated form of the initiation factor PfeIF2 (i.e., PfeIF2α-P) which inhibits its own guanine exchange factor PfeIF2B. Translation repression is required for blood stages to complete the erythrocytic cycle and has recently been shown to play a role in the enhanced stress response observed in K13 mutant ring stages. Beyond this, translation repression is required for latency in sporozoites, and likely also in dormant, liver-stage hypnozoites that cause relapsing infection by P. vivax. Unfortunately, a general lack of useful pharmacological tools has hampered studies of these wider-ranging effects of translation repression in relevant cellular and animal models. Here we propose a lead identification effort focused on two complementary targets in the parasite stress response pathway, the PfeIF2α kinase PfPK4 and the guanine exchange factor PfeIF2B (the predicted GEF for PfeIF2α). Based on strong preliminary data, we predict that either PK4 inhibition or GEF activation will inhibit translation repression and that these two pharmacologies will be synergistic in the pathway. The expected outcome of the project is specific PK4 inhibitors and PfeIF2B activators with bona fide on- pathway activity in parasites. In addition to providing tractable lead compounds for further lead discovery efforts, the project will generate crucial pharmacological tools that can be used to study the broader-ranging roles of translation repression in malaria infectivity, dormancy, and transmission outside the scope of this project.