Small-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding

Abstract

Measles virus (MeV) is a highly contagious pathogen that enters the human host via the respiratory route. Besides acute pathologies including fever, cough and the characteristic measles rash, the infection of lymphocytes leads to substantial immunosuppression that can exacerbate the outcome of infections with additional pathogens. Despite the availability of effective vaccine prophylaxis, measles outbreaks continue to occur worldwide. We demonstrate that prophylactic and post-exposure therapeutic treatment with an orally bioavailable small-molecule polymerase inhibitor, ERDRP-0519, prevents measles disease in squirrel monkeys (Saimiri sciureus). Treatment initiation at the onset of clinical signs reduced virus shedding, which may support outbreak control. Results show that this clinical candidate has the potential to alleviate clinical measles and augment measles virus eradication.

Repurposing an In Vitro Measles Virus Dissemination Assay for Screening of Antiviral Compounds

“…Surprisingly, all ferrets in the post-exposure treatment group survived and only experienced mild lymphopenia. Next, ERDRP-0159 was also tested for its potential as an MV inhibitor in squirrel monkeys infected with a clinical MV isolate from Germany [52]. As measles is usually not lethal in monkeys, the investigators used rash, viral titers in PBMC, viral titers in nose swabs and leukopenia as a measure of efficacy.…”

“…Ribavirin and ribavirin-derivatives and -analogs [33][34][35][36][37][38][39][40] Ring-expanded purine nucleosides [34] Remdesivir [41,42] Favipiravir (T-705) [43,44] Derivatives of R1479 [45] Pyrazofurin [36] 3-Deazaguanine and its carbocyclic analog [36,38,40] 6-Azauridine [36] 5'-nor carbocyclic adenosine analogues [46] L-dideoxy bicyclic nucleoside analogs [47] Non-nucleoside polymerase inhibitors AS136a [48,49] ERDRP-0519 [49][50][51][52] GHP-88309 [53] Fusion and entry inhibitors Peptide inhibitors Z-D-Phe-L-Phe-L-Gly (FIP) [54][55][56][57][58] HRC-based peptides: M1, M2, M3, M4, M1EK, M2EK, M3EK, M4EK [59] HRC-lipopeptides [60][61][62][63][64] FIP-lipopeptides [64] FIP-HRC-lipopeptides [64] Nonpeptidic small molecules [65] 16677 [66] 3G [63,67] AS-48 [56][57]…”

“…Edmonston [46,65,81,82,85] rMV-Edm [48,50,66] rMV-Edm-GFP [44,68] MV wild-type(-derived) MV/Brazil/001/991 [72] MVi/Alaska.USA/16.00 [48][49][50]53,99] MVi/Ibadan.NIE/97/1 [48,50] MVi-Amsterdam.NET/49.97 [48] MVi/Maryland.USA/77 [50] MVi/Illinois.USA/46.02 [50] MVi/NewJersey.USA/94/1 [50,52] MVi/Illinois.USA/50.99 [50] MVi/Kansas.USA/43.00 [57,65] MV Hallé strain [55] Chicago-1 [46] culture adapted Chicago 1 [79] MV-Ibd, MV-JM77, MV-NJ, MV-III 99, MV-Vic/Aus, MV-Amster.NET, MV Gresik, MV-Alaska [66] rMV-IC323-eGFP [87] Undefined MV [53,77,86,88]…”

Anno 2021: Which antivirals for the coming decade?

“…Recently, the in vivo oral efficacy of this compound was further validated in non-human primates known to develop a human measles-like disease. 238 Prophylactic and post-exposure therapeutic treatment of squirrel monkeys ( Saimiri sciureus ) reduced virus shedding and prevented measles disease. Mechanistically, ERDRP-0519 was demonstrated to target the MeV polymerase and specifically inhibit all phosphodiester bond formation during both the de novo initiation of RNA synthesis and RNA elongation steps.…”

The Sphingolipid Inhibitors Ceranib-2 and SKI-II Reduce Measles Virus Replication in Primary Human Lymphocytes: Effects on mTORC1 Downstream Signaling

“…Due to the ongoing SARS-coronavirus-2 pandemic causing COVID-19, it is expected that measles vaccination campaigns are ceased and the number of cases will rise ( Roberts, 2020 ). Although promising efficacious inhibitors have been characterized ( Cox et al, 2020 ; Wittwer et al, 2021 ), only limited treatment options such as the use of ribavirin are in place and an efficient antiviral therapy against acute or persistent MV infections including subacute sclerosing panencephalitis (SSPE) is not yet clinically available ( Reuter and Schneider-Schaulies, 2010 ). Alternative treatment options supporting the available ones would be desirable.…”