Open Labs Fellow/s

Abbas Hussein Khamis Al Temimi

GSK’s contribution

This project will strongly benefit from the expertise at GSK in medicinal chemistry and Plasmodium infections, including:
1) the availability of a large library of active compounds;
2) vast experience in drug metabolism and pharmacokinetics studies; and
3) the availability of fully functional insectary and mosquito infection facilities and
4) Malaria in vivo models.
In addition, the lead compounds characterized during the project will be produced in compliance with pharmacological industry requirements necessary to facilitate follow-on clinical development and testing.

Project Description

We have described a mechanism by which the Plasmodium expressed cytokine Macrophage Migration inhibitory Factor (PMIF) acts to prevent the acquisition of immunologic memory by activating the host MIF receptor CD74 to establish severe malaria and parasite replication. Immunoneutralization or genetic deletion of PMIF, strictly conserved in all Plasmodium species, improves malaria immunologic memory, reduces parasite burden, and protects from severe malaria.

Moreover, we have shown in genetic PMIF deficiency experiments that malaria protection and development can be recapitulated with a small-molecule antagonist developed by our group. This novel molecule, called 26k, was identified by leveraging the unique features of PMIF structural biology. It specifically blocks PMIF interaction with its host receptor CD74, inhibiting parasite replication in the host liver and protecting from severe malaria.

We hypothesize that such a PMIF inhibitor provides a unique approach for interfering with a parasite-specific mechanism for suppressing host immunity and offers a new tool for combating Plasmodium infection.

This project aims to identify better quality and pharmacologically tractable PMIF antagonists for lead optimization programs and will provide a proof-of-concept that PMIF pharmacological inhibition increases memory immunity to Plasmodium infection. We will accomplish our objective by pursuing the following Specific

Aims:
Aim 1: Identification and optimization of novel PMIF inhibitors.
Aim 2: Evaluation of lead PMIF inhibitors in experimental models of Plasmodium infection.
Aim 3: Evaluation of the full therapeutic potential of PMIF inhibitors.

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