Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro
Todd G. Smith,
Felix R. Jackson,
Clint N. Morgan,
William C. Carson,
Brock E. Martin,
Nadia Gallardo-Romero,
James A. Ellison,
Lauren Greenberg,
Thomas Hodge,
Luis Squiquera,
Jamie Sulley,
Victoria A. Olson,
Christina L. Hutson
Affiliations
Todd G. Smith
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Felix R. Jackson
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Clint N. Morgan
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
William C. Carson
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Brock E. Martin
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Nadia Gallardo-Romero
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
James A. Ellison
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Lauren Greenberg
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Thomas Hodge
Tamir Biotechnology, Inc. 12625 High Bluff Drive Suite 113, San Diego, CA 92130, USA
Luis Squiquera
Tamir Biotechnology, Inc. 12625 High Bluff Drive Suite 113, San Diego, CA 92130, USA
Jamie Sulley
Tamir Biotechnology, Inc. 12625 High Bluff Drive Suite 113, San Diego, CA 92130, USA
Victoria A. Olson
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Christina L. Hutson
Poxvirus and Rabies Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Atlanta, GA 30329, USA
Currently, no rabies virus-specific antiviral drugs are available. Ranpirnase has strong antitumor and antiviral properties associated with its ribonuclease activity. TMR-001, a proprietary bulk drug substance solution of ranpirnase, was evaluated against rabies virus in three cell types: mouse neuroblastoma, BSR (baby hamster kidney cells), and bat primary fibroblast cells. When TMR-001 was added to cell monolayers 24 h preinfection, rabies virus release was inhibited for all cell types at three time points postinfection. TMR-001 treatment simultaneous with infection and 24 h postinfection effectively inhibited rabies virus release in the supernatant and cell-to-cell spread with 50% inhibitory concentrations of 0.2−2 nM and 20−600 nM, respectively. TMR-001 was administered at 0.1 mg/kg via intraperitoneal, intramuscular, or intravenous routes to Syrian hamsters beginning 24 h before a lethal rabies virus challenge and continuing once per day for up to 10 days. TMR-001 at this dose, formulation, and route of delivery did not prevent rabies virus transit from the periphery to the central nervous system in this model (n = 32). Further aspects of local controlled delivery of other active formulations or dose concentrations of TMR-001 or ribonuclease analogues should be investigated for this class of drugs as a rabies antiviral therapeutic.
