DRUG DISCOVERY RATIONALE
The collective global burden of tuberculosis, malaria and schistosomiasis accounts for approximately 460 million infections and nearly two million deaths on an annual basis. However, the impact of these neglected tropical disease (NTDs), and others, cannot be simply measured with these metrics. Importantly, NTDs disproportionately affect low-resource countries and can inflict socioeconomic inequalities within endemic regions. Interventions, ranging from public health education, vector control strategies (when applicable), therapeutics and vaccines, are all critical to the control, elimination and eventual eradication of NTDs. Therapeutics tend to favor small molecules because they can be administered orally, stably stored at ambient conditions for years, and have a relatively low cost of goods. These criteria are essential for the successful development, deployment, and sustained use within endemic regions. Of course, the continual emergence of drug-resistant pathogens underscores the importance of maintaining a robust pipeline of new medicines. Our team is focused on the identification and preclinical development of novel, small-molecule interventions that can contribute to the global drug discovery pipeline to combat the ramifications of endemic NTDs.
MALARIA
Despite excellent efforts from the Medicines for Malaria Venture (MMV) and the malaria drug discovery community, additional strategies and medicines are still needed to further reduce the malaria prevalence throughout Africa, Southeast Asia and South America. The Calibr team is taking multiple approaches to contribute to the needed armamentarium of interventions:
Inhibitors of novel Plasmodium drug targets. In collaboration with the Malaria Drug Accelerator (MalDA), a Bill & Melinda Gates Foundation-funded consortium of malaria researchers, Calibr is a contributing consortium member committed to translating validated drug targets into early drug discovery.
Long-acting injectables, a new strategy for malaria prevention in low-endemic regions with seasonal transmission. Prodrug or salts of approved antimalarials are formulated for parenteral administration to overcome the limitations of repeated oral administration and to extend efficacious exposure from a single injection for >1 month (and ideally 3 months).
Liver-stage inhibitors for malaria prevention. Development of small-molecule inhibitors to eliminate parasite development within the liver before progression into the symptomatic blood stages.
Endectosides, a transmission-blocking strategy. Targeting the development of oral, systemic mosquitocidal compounds that will subsequently kill mosquitoes after a blood meal to help reduce vector-to-human transmission.
Inhibitors of novel Plasmodium drug targets. In collaboration with the Malaria Drug Accelerator (MalDA), a Bill & Melinda Gates Foundation-funded consortium of malaria researchers, Calibr is a contributing consortium member committed to translating validated drug targets into early drug discovery.
Long-acting injectables, a new strategy for malaria prevention in low-endemic regions with seasonal transmission. Prodrug or salts of approved antimalarials are formulated for parenteral administration to overcome the limitations of repeated oral administration and to extend efficacious exposure from a single injection for >1 month (and ideally 3 months).
Liver-stage inhibitors for malaria prevention. Development of small-molecule inhibitors to eliminate parasite development within the liver before progression into the symptomatic blood stages.
Endectosides, a transmission-blocking strategy. Targeting the development of oral, systemic mosquitocidal compounds that will subsequently kill mosquitoes after a blood meal to help reduce vector-to-human transmission.
TUBERCULOSIS
Much like the malaria drug discovery program, Calibr participates in the Tuberculosis Drug Accelerator (TBDA), which is also supported by The Bill & Melinda Gates Foundation. The primary goal of the TBDA is to support development of new frontline drugs that will decrease treatment to three months or less. This expansive consortium involves numerous key academic and pharma partners to drive drug development against high-value drug targets. In collaboration with many TBDA partners, Calibr is taking the following strategies to develop novel treatments:
Innovative chemistry. Scripps Research is renowned for its world-class chemistry, which creates a unique opportunity for the Calibr infectious disease team to apply these approaches to drug develop for differentiated medicines with the potential to have superior attributes compared to traditional medicinal chemistry.
Targeting cholesterol catabolism. In addition, the Calibr TB team, in collaboration with researchers at Cornell University, has developed a promising preclinical candidate with the potential to sterilize infected mice when administered in combination with pretomanid and bedaquiline, a recently approved combination therapy.
Innovative chemistry. Scripps Research is renowned for its world-class chemistry, which creates a unique opportunity for the Calibr infectious disease team to apply these approaches to drug develop for differentiated medicines with the potential to have superior attributes compared to traditional medicinal chemistry.
Targeting cholesterol catabolism. In addition, the Calibr TB team, in collaboration with researchers at Cornell University, has developed a promising preclinical candidate with the potential to sterilize infected mice when administered in combination with pretomanid and bedaquiline, a recently approved combination therapy.
SCHISTOSOMIASIS
Under funding from the Wellcome Trust, we formed an integrated set of key academic partners with diverse expertise in Schistosome biology to complement Calibr's drug discovery acumen.
ReFRAME library. The ReFRAME library is being screened against adult S. mansoni to identify drug repurposing opportunities and to build a collection of elegant chemical tools to investigate the biology of the Schistosomes. We expect these chemical tools will be powerful probes to assist target identification and discovery high-value drug targets that we can translate into a high-throughput biochemical screen.
ReFRAME library. The ReFRAME library is being screened against adult S. mansoni to identify drug repurposing opportunities and to build a collection of elegant chemical tools to investigate the biology of the Schistosomes. We expect these chemical tools will be powerful probes to assist target identification and discovery high-value drug targets that we can translate into a high-throughput biochemical screen.
Additional drug discovery programs
Funding from Wellcome Trust Innovations Flagships (WT) and Bill & Melinda Gates Foundation (BMGF) support a significant investment against a diverse set of important pathogens. The drug discovery programs for these additional NTDs are directed by other team leaders in the Infectious Disease program and target:
- Cryptosporidiosis (WT team leader: Melissa Love)
- Chagas disease (WT team leader: Malina Bakowski)
- Leishmaniasis (WT team leader: Malina Bakowski)
- Dengue fever (WT team leader: Karen Wolff)
- COVID-19 (BMGF team leader: Karen Wolff)