An Isomer of Galidesivir That Potently Inhibits Influenza Viruses and Members of the Bunyavirales Order

Kevin J Sparrow; Rinu Shrestha; James M Wood; Keith Clinch; Brett L Hurst; Hong Wang; Brian B Gowen; Justin G Julander; E Bart Tarbet; Alice M McSweeney; Vernon K Ward; Gary B Evans; Lawrence D Harris

doi:10.1021/acsmedchemlett.3c00048

An Isomer of Galidesivir That Potently Inhibits Influenza Viruses and Members of the Bunyavirales Order

ACS Med Chem Lett. 2023 Mar 30;14(4):506-513. doi: 10.1021/acsmedchemlett.3c00048. eCollection 2023 Apr 13.

Authors

Kevin J Sparrow¹, Rinu Shrestha^{1

2}, James M Wood^{1

2}, Keith Clinch¹, Brett L Hurst³, Hong Wang³, Brian B Gowen³, Justin G Julander³, E Bart Tarbet³, Alice M McSweeney⁴, Vernon K Ward^{4

2}, Gary B Evans^{1

2}, Lawrence D Harris^{1

2}

Affiliations

¹ Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Road, Lower Hutt 5040, New Zealand.
² The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1142, New Zealand.
³ Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600, United States.
⁴ Department of Microbiology & Immunology, University of Otago, PO Box 56, Dunedin 9054, New Zealand.

Abstract

We report for the first time the antiviral activities of two iminovirs (antiviral imino-C-nucleosides) 1 and 2, structurally related to galidesivir (Immucillin A, BCX4430). An iminovir containing the 4-aminopyrrolo[2,1-f][1,2,4-triazine] nucleobase found in remdesivir exhibited submicromolar inhibition of multiple strains of influenza A and B viruses, as well as members of the Bunyavirales order. We also report the first syntheses of ProTide prodrugs of iminovir monophosphates, which unexpectedly displayed poorer viral inhibition than their parent nucleosides in vitro. An efficient synthesis of the 4-aminopyrrolo[2,1-f][1,2,4-triazine]-containing iminovir 2 was developed to enable preliminary in vivo studies, wherein it displayed significant toxicity in BALB/c mice and limited protection against influenza. Further modification of this anti-influenza iminovir will therefore be required to improve its therapeutic value.

Abstract

Grants and funding