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Principal Investigator: Gang Lin
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $735,318
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
In 2020, with over 250 million debilitating cases and over half a million deaths, mostly in young children,
malaria is a persistent global health crisis. The malaria-causing parasite Plasmodium falciparum (Pf)
has developed resistance to most antimalarial drug deployed, including the backbone artemisinins
(ARTs). ART and its semi-synthetic analogs are considered essential for malaria treatment. ARTs are
prodrugs that are activated within the parasites to form a reactive radical that covalently attacks
proteins, lipids and other cellular constituents. ART resistance is widespread in Southeast Asia and has
been reported in Africa. ART combination therapy (ACT) is a mainstay for treatment of malaria, but its
efficacy can be derailed when a two-drug combination becomes de facto monotherapy. Moreover,
extended exposure of Pf to ACTs induces multidrug tolerance. We recently showed that inhibitors
specific for the Pf proteasome (Pf20S) kill Pf in each stage of its life cycle and synergize with ART,
overcoming ART resistance. This proposal builds on our discovery that a covalent hybrid of an ART
analogue and a Pf20S inhibitor that we call an artezomib (ATZ) can enhance ART action and overcome
resistance to each of its components. We have synthesized ATZs that are more potent Pf20S inhibitors
than their component Pf20S inhibitor. They not only kill wild type and ART-resistant (K13 mutant) Pf, Pf
with proteasome mutations that confer resistance to the Pf20S inhibitor, but also kill Pf that expresses
both ART-resistant and PI-resistant mutations. We propose the following mechanism by which ATZs
overcome resistance to the Pf20S inhibitor within them: We found that upon activation of ATZ in the
parasites, the ART component binds Pf proteins, like activated ART itself. The Pf ubiquitin proteasome
system digests ATZ-bound proteins into oligopeptides, some of which display the Pf inhibitor
component of the ATZ. We hypothesize that extended contact of ATZ-bearing peptides within the
Pf20S active site augments the binding of the Pf20S inhibitor component of the ATZ, overcoming the
decreased binding otherwise conferred by Pf20S point mutations. Thus, an ATZ can overcome
resistance to each of its components. In mouse models of malaria, an ATZ drove P. berghei below the
limit of detection and suppressed recrudescence of a P. berghei ART-resistant K13 mutant and doing
so better than ART. In Aim 1 of this proposal, we will conduct lead optimization to improve ATZs'
potency, selectivity and ATZs' pharmacokinetic properties. In Aim 2, we will explore ATZs' mechanism
of action; attempt to select for ATZ-resistant parasites; determine the frequency and mechanism of
resistance, if any; and study antimalarial activity of ATZs in stages of the Pf life cycle when ART alone
is ineffective. Aim 3 will test the efficacy of ATZs in mice, including humanized mice infected with Pf.
.
Terms: <0-11 years old><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><AIDS Virus><APF-1><ATP-Dependent Proteolysis Factor 1><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Sites><Africa><African><Anti-malarials><Artemisinins><Assay><Binding><Binding Proteins><Bioassay><Bioavailability><Biochemical><Biological><Biological Assay><Biological Availability><Body Tissues><Cancers><Cell Body><Cells><Cessation of life><Chemicals><Child><Child Youth><Children (0-21)><Chlorohemin><Clinical><Combined Modality Therapy><Communicable Diseases><Death><Distal><Drug Combinations><Drug Kinetics><Drug Precursors><Drug resistance><Drugs><Exposure to><Ferriheme Chloride><Ferriprotoporphyrin IX Chloride><Frequencies><Genetic Alteration><Genetic Change><Genetic defect><Goals><HIV><HMG-20><Hemin><High Mobility Protein 20><Human Immunodeficiency Viruses><Hybrids><In Vitro><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Investigation><LAV-HTLV-III><Life Cycle><Life Cycle Stages><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><Lymphadenopathy-Associated Virus><Lytotoxicity><Macropain><Macroxyproteinase><Malaria><Malignant Neoplasms><Malignant Tumor><Medication><Mice><Mice Mammals><Modeling><Molecular Interaction><Multicatalytic Proteinase><Multienzyme Complexes><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><Oligopeptides><Oral><Organism><P falciparum><P. falciparum><P.falciparum><Paludism><Parasite resistance><Parasites><Penetration><Peptides><Pharmaceutical Preparations><Pharmacokinetics><Physiologic Availability><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Point Mutation><Prevention><Pro-Drugs><Process><Prodrugs><Property><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteasome Inhibitor><Protein Binding><Proteins><Proteosome><Protohemin><Recrudescences><Reporting><Resistance><Resistance development><Resistant development><Site><Southeast Asia><Southeastern Asia><Spinal Column><Spine><Structure-Activity Relationship><System><TB therapy><TB treatment><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Ubiquitin><Vertebral column><Virus-HIV><analog><anti-malarial agents><anti-malarial drugs><arteannuin><artemisinine><backbone><biologic><bound protein><chemical structure function><combination therapy><combined modality treatment><combined treatment><cytotoxicity><detection limit><developing resistance><drug resistant><drug/agent><efficacy study><efficacy testing><enzyme complex><genome mutation><global health><high risk><humanized mice><humanized mouse><improved><in vivo><inhibitor><kids><lead optimization><life course><living system><malignancy><mouse model><multi-drug tolerance><multi-modal therapy><multi-modal treatment><multicatalytic endopeptidase complex><multidrug tolerance><multiple drug tolerance><murine model><mutant><neoplasm/cancer><novel><oxidative damage><oxidative injury><parasite resistant><pharmacophore><prevent><preventing><qinghaosu><quing hau sau><quinghaosu><resistance mechanism><resistance mutation><resistance to Drug><resistance to Parasite><resistant><resistant mechanism><resistant mutation><resistant parasite><resistant to Drug><resistant to Parasite><standard care><standard treatment><structure function relationship><success><synergism><tolerant to multiple drugs><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><tuberculosis therapy><tuberculosis treatment><youngster>