The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks

Samby, Kirandeep; Besson, Dominique; Dutta, Anirban; Patra, Buddhadev; Doy, Angelique; Glossop, Paul A.; Mills, James E.; Whitlock, Gavin A.; Huijsduijnen, Rob Hooft van; Monaco, Alessandra; Bilbe, Graeme; Mowbray, Charles E.; Perry, Benjamin; Adam, Anna; Wells, Timothy N. C.; Willis, Paul

doi:10.1021/acsinfecdis.1c00527

Cited by 23 publications

(27 citation statements)

References 29 publications

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“…In this study, we describe the development of a stable CHIKV replicon cell line, the BHK-21-T7-Gluc-nSP-CHIKV-99650, which harbors a replicative replicon expressing Gaussia luciferase (GLuc) as a reporter gene. Using this cell line in replicon-based assays, we evaluated three MMV/DNDi small-molecule libraries, the Pandemic Response (PRB), Pathogen, and COVID boxes, all containing molecules either marketed or in development, with known or predicted antiviral, antifungal, or antibacterial activities [ 21 , 22 , 23 ], for the identification of anti-CHIKV agents. From the tested molecules, the antifungal itraconazole was the most effective, exhibiting a selectivity index (SI) of > 312.…”

Section: Introductionmentioning

confidence: 99%

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Policastro

Dolci

Godoy

et al. 2022

Viruses

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Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.

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Section: Introductionmentioning

confidence: 99%

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Policastro

Dolci

Godoy

et al. 2022

Viruses

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“…0×10 −4 M, 5.0×10 −5 M and 7.5×10 −5 M as well as the L4 motility assay at 1.0×10 −4 M. These compounds were MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531. Four are previously described antivirals and two have antibacterial activity (Samby et al, 2022). Vorapaxar is a human approved drug while diphyllin, ABX464 and rubitecan are in various human clinical trials (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…It includes 400 drug-like compounds that are either already on the market or in various stages of research for uses other than anthelmintics. The library was selected by experts from Academia and Industry with the aim of pursuing an Open Source approach to discovering new chemical leads that could impact on neglected, pandemic-scale diseases with unmet clinical needs (Samby et al, 2022). The library contains 201 antibacterial compounds, 153 antivirals, and 46 antifungals.…”

Section: Introductionmentioning

confidence: 99%

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Screening the Medicines for Malaria Pandemic Response Box chemical library onCaenorhabditis elegansidentifies re-profiled candidate anthelmintic drug leads

Nick

Partridge

Forman

et al. 2022

Preprint

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The 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organism Caenorhabditis elegans. The 400 compound Medicines for Malaria Pandemic Response Box library was screened with each compound tested initially at 1.0 x 10-4 M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth / motility assay and in an L4 motility assay. For vorapaxar, an EC50 of 5.7 x 10-7 M was observed, a value comparable to some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematode C. elegans makes this a useful approach to identify chemical leads and complement the often lower-throughput experiments on parasitic nematode models.

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“…The PRB is a collection of 400 structurally diverse compounds stratified by antibacterial, antiviral, and antifungal activities (201, 153, and 46 compounds, respectively) ( 18 ). A screening cascade was developed to streamline the potential compounds with significant QSI activity by filtering them stepwise ( Fig.…”

Section: Observationmentioning

confidence: 99%

Screening of the Medicines for Malaria Venture Pandemic Response Box for Discovery of Antivirulent Drug against Pseudomonas aeruginosa

et al. 2022

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The rise of drug-resistant pathogens as well as overuse and misuse of antibiotics threatens modern medicine as the number of effective antimicrobial drugs steadily decreases. Given the nature of antimicrobial resistance development under intense selective pressure such as the one posed by pathogen-eliminating antibiotics, new treatment options which could slow down the emergence of resistance are urgently needed.

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The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks

Cited by 23 publications

References 29 publications

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication

Screening the Medicines for Malaria Pandemic Response Box chemical library onCaenorhabditis elegansidentifies re-profiled candidate anthelmintic drug leads

Screening of the Medicines for Malaria Venture Pandemic Response Box for Discovery of Antivirulent Drug against Pseudomonas aeruginosa

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