Heather Gaona

Walter Reed Army Institute of Research

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Mara Kreishman-Deitrick

Walter Reed Army Institute of Research

Victor Meléndez

Allina Health

Qigui Li

Shandong Agricultural University

Lisa Xie

Walter Reed Army Institute of Research

Susan E. Leed

Walter Reed Army Institute of Research

Norma Roncal

Walter Reed Army Institute of Research

Sean R. Marcsisin

Walter Reed Army Institute of Research

Chau Vuong

Walter Reed Army Institute of Research

Brittney Potter

Walter Reed Army Institute of Research

Jason Sousa

Walter Reed Army Institute of Research

Cooperative Institutions

Walter Reed Army Institute of Research

Johns Hopkins University

United States Army Medical Research Directorate - Africa

Portland State University

Portland VA Medical Center

VA Portland Health Care System

Albert Einstein College of Medicine

Oregon Health & Science University

Kenya Medical Research Institute

Madigan Army Medical Center

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Targeting the Fatty Acid Biosynthesis Enzyme, β-Ketoacyl−Acyl Carrier Protein Synthase III (PfKASIII), in the Identification of Novel Antimalarial Agents

Journal of Medicinal Chemistry (2009)

Patricia Lee Jayendra B. Bhonsle Heather Gaona D.P. Huddler Tiffany N. Heady

The importance of fatty acids to the human malaria parasite, Plasmodium falciparum, and differences due to a type I fatty acid synthesis (FAS) pathway in the parasite, make it an attractive drug target. In the present study, we developed and a utilized a pharmacophore to select compounds for testing against PfKASIII, the initiating enzyme of FAS. This effort identified several PfKASIII inhibitors that grouped into various chemical classes of sulfides, sulfonamides, and sulfonyls. Approximately 60% of the submicromolar inhibitors of PfKASIII inhibited in vitro growth of the malaria parasite. These compounds inhibited both drug sensitive and resistant parasites and testing against a mammalian cell line revealed an encouraging in vitro therapeutic index for the most active compounds. Docking studies into the active site of PfKASIII suggest a potential binding mode that exploits amino acid residues at the mouth of the substrate tunnel.

Acyl carrier protein

Docking (animal)

10.1021/jm8008103

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Citations (48)

Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials

Journal of Medicinal Chemistry (2020)

Papireddy Kancharla Rozalia A. Dodean Yuexin Li Sovitj Pou Brandon Pybus

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.

Acridone

Broad spectrum

10.1021/acs.jmedchem.0c00539

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Citations (9)

Discovery and Structural Optimization of Acridones as Broad-Spectrum Antimalarials

Journal of Medicinal Chemistry (2019)

Rozalia A. Dodean Papireddy Kancharla Yuexin Li Victor Meléndez Lisa Read

Malaria remains one of the deadliest diseases in the world today. Novel chemoprophylactic and chemotherapeutic antimalarials are needed to support the renewed eradication agenda. We have discovered a novel antimalarial acridone chemotype with dual-stage activity against both liver-stage and blood-stage malaria. Several lead compounds generated from structural optimization of a large library of novel acridones exhibit efficacy in the following systems: (1) picomolar inhibition of in vitro Plasmodium falciparum blood-stage growth against multidrug-resistant parasites; (2) curative efficacy after oral administration in an erythrocytic Plasmodium yoelii murine malaria model; (3) prevention of in vitro Plasmodium berghei sporozoite-induced development in human hepatocytes; and (4) protection of in vivo P. berghei sporozoite-induced infection in mice. This study offers the first account of liver-stage antimalarial activity in an acridone chemotype. Details of the design, chemistry, structure–activity relationships, safety, metabolic/pharmacokinetic studies, and mechanistic investigation are presented herein.

Acridone

Plasmodium berghei

Plasmodium yoelii

Hemozoin

Plasmodium (life cycle)

10.1021/acs.jmedchem.8b01961

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Citations (16)

Assessment of the Worldwide Antimalarial Resistance Network Standardized Procedure for In Vitro Malaria Drug Sensitivity Testing Using SYBR Green Assay for Field Samples with Various Initial Parasitemia Levels

Antimicrobial Agents and Chemotherapy (2016)

Agnes C. Cheruiyot Jennifer M. Auschwitz Patricia Lee Redemptah Yeda Charles O. Okello

The malaria SYBR green assay, which is used to profilein vitrodrug susceptibility ofPlasmodium falciparum, is a reliable drug screening and surveillance tool. Malaria field surveillance efforts provide isolates with various low levels of parasitemia. To be advantageous, malaria drug sensitivity assays should perform reproducibly among various starting parasitemia levels rather than at one fixed initial value. We examined the SYBR green assay standardized procedure developed by the Worldwide Antimalarial Resistance Network (WWARN) for its sensitivity and ability to accurately determine the drug concentration that inhibits parasite growth by 50% (IC50) in samples with a range of initial parasitemia levels. The initial sensitivity determination of the WWARN procedure yielded a detection limit of 0.019% parasitemia.P. falciparumlaboratory strains and field isolates with various levels of initial parasitemia were then subjected to a range of doses of common antimalarials. The IC50s were comparable for laboratory strains with between 0.0375% and 0.6% parasitemia and for field isolates with between 0.075% and 0.6% parasitemia for all drugs tested. Furthermore, assay quality (Z') analysis indicated that the WWARN procedure displays high robustness, allowing for drug testing of malaria field samples within the derived range of initial parasitemia. The use of the WWARN procedure should allow for the inclusion of more malaria field samples in malaria drug sensitivity screens that would have otherwise been excluded due to low initial parasitemia levels.

10.1128/aac.00527-15

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Citations (28)

Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations

Journal of Pharmacological and Toxicological Methods (2014)

Xiannu Jin ThuLan Luong Necole Reese Heather Gaona Vanessa Collazo-Velez

ADME

Drug Development

Cell permeability

P-glycoprotein

10.1016/j.vascn.2014.08.002

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Citations (86)