A collaboration aimed at identifying and developing potential new antimalarial drug candidate drugs has been announced between Walter and Eliza Hall Institute for Medical Research (WEHI) in Melbourne, Australia, and Janssen Pharmaceutica, with assistance from Johnson & Johnson Innovation.

The collaboration has already discovered promising compounds with antimalarial activity from among 80,000 drug-like molecules in the Janssen Jumpstarter Compound Library, a collection of drug-like compounds designed to fast-track discovery of new medicines.

Promising candidates are now being developed toward potential antimalarial drugs, which could lead to new weapons in the armamentarium against malaria, WEHI announced in a press release to mark World Malaria Day on April 25, 2021.

According to WHO, an estimated 220 million people worldwide contract malaria each year, resulting in approximately 410,000 deaths, predominantly children.

"Artemisinin combination therapies are currently the frontline treatments for malaria, as these are highly effective, have very few side effects, and are highly affordable," said Alan Cowman, a professor and head of WEHI's malaria research program.

However, "this dependence on and widespread use of artemisinin, in addition to drug compliance issues, has caused the emergence of resistance in malaria endemic regions, limiting its effectiveness."

Resistance

"Artemisinin resistance emerged some 13 years ago, and has rapidly spread throughout Southeast Asia and, of particular concern, last year the first cases of artemisinin resistance emerged in sub-Saharan Africa, where malaria causes the greatest burden and human suffering," said Cowman.

This resistance to currently used antimalarials represents one of the greatest threats to global malaria control, with new medicines being urgently needed. However, developing new treatments to prevent or treat malaria requires expertise in the biology of the Plasmodium malaria parasite, its mosquito vector and their interactions with humans.

WEHI has considerable experience in this regard, combining expertise in drug development and malaria biology to ensure newly developed drugs have optimal chances of success and target key Plasmodium proteins.

The opportunity to access the Jump-starter Compound Library in 2016 enhanced the search for new antimalarials, with newly identified compounds and their key proteins now being investigated by WEHI in collaboration with Janssen.

"The Janssen library has been expertly curated to contain structurally diverse small molecules with drug-like characteristics that make them ideal candidates for antimalarial drug development," noted Cowman.

"These attributes include attractive physical properties that ensure they are 'pre-primed' to have efficacy in malaria models," he told BioWorld Science.

"This collaboration has enabled us to access compounds that can be developed into new medicines and, with support from Johnson & Johnson Innovation, we have shown that this library contains multiple compounds with antimalarial activity, which could be developed into new antimalarial drug candidates."

Antimalarial candidates

Brad Sleebs, laboratory head of the Chemical Biology Division at WEHI, led the team modifying the library's potential antimalarial compounds to enhance their activity and medicinal suitability.

Working with the Janssen Discovery Chemistry team to progress this research phase, WEHI researchers have identified promising compounds and shown how they stop malaria growth.

To this end, "we use various cutting-edge malaria models that replicate the malaria lifecycle, including mosquito to human transmission," said Sleebs.

"These models are important for informing which part of the malaria lifecycle these drugs target and how they will be used clinically to treat malaria," he told BioWorld.

"Compounds identified from the Janssen library form several drug-like structural classes which are ideal for development and optimization into drugs, with optimization typically taking 3-4 years to generate a drug candidate suitable for human clinical trials."

The research collaboration has been boosted by the involvement of the not-for-profit Medicines for Malaria Venture (MMV), which aims to reduce the malarial burden and eventually eradicate the disease.

MMV has provided critical advice regarding chemical compound design and ensuring that drugs being developed at WEHI meet their standards and do not replicate malarial research elsewhere.

"Due to our valuable collaboration with MMV, we can be confident we are working in a unique research space, as MMV has provided access to a global network of malaria researchers and assays," Sleebs noted.

"WEHI has a strong track record in malaria biology, drug screening and medicinal chemistry, which is complemented by our collaborators' skills, yielding promising antimalarial drug candidates that we are now assessing in preclinical models."

"We primarily test our promising drug candidates against the malarial parasite in the culture dish to test how effective they are at killing the malaria parasite," explained Sleebs.

"To replicate transmission of Plasmodium between mosquito and its human host, we have a specialized facility that houses and rears the mosquito vector," he said.

"We use mosquito models to test whether drugs under development will be effective at blocking the spread of the parasite in malaria endemic communities and are hopeful our newly developed drugs will critically contribute to the worldwide effort to eliminate malaria."