Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

Pharmaceutical research
Volume 37, 2020, Issue 4, 71

Ekins, S.; Lane, T. R.; Madrid, P. B.

Abstract

For the last 50 years we have known of a broad-spectrum agent tilorone dihydrochloride (Tilorone). This is a small-molecule orally bioavailable drug that was originally discovered in the USA and is currently used clinically as an antiviral in Russia and the Ukraine. Over the years there have been numerous clinical and non-clinical reports of its broad spectrum of antiviral activity. More recently we have identified additional promising antiviral activities against Middle East Respiratory Syndrome, Chikungunya, Ebola and Marburg which highlights that this old drug may have other uses against new viruses. This may in turn inform the types of drugs that we need for virus outbreaks such as for the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tilorone has been long neglected by the west in many respects but it deserves further reassessment in light of current and future needs for broad-spectrum antivirals.

Keywords

Antiviral, broad spectrum, interferon inducers, respiratory virus infections

Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease

Virology
Volume 517, April 2018, Pages 98-107

Madeline G. Douglas, Jacob F. Kocher, Trevor Scobey, Ralph S. Baric, Adam S. Cockrell

Abstract

We recently established a mouse model (288–330+/+) that developed acute respiratory disease resembling human pathology following infection with a high dose (5 × 106 PFU) of mouse-adapted MERS-CoV (icMERSma1). Although this high dose conferred fatal respiratory disease in mice, achieving similar pathology at lower viral doses may more closely reflect naturally acquired infections. Through continued adaptive evolution of icMERSma1 we generated a novel mouse-adapted MERS-CoV (maM35c4) capable of achieving severe respiratory disease at doses between 103 and 105 PFU. Novel mutations were identified in the maM35c4 genome that may be responsible for eliciting etiologies of acute respiratory distress syndrome at 10–1000 fold lower viral doses. Importantly, comparative genetics of the two mouse-adapted MERS strains allowed us to identify specific mutations that remained fixed through an additional 20 cycles of adaptive evolution. Our data indicate that the extent of MERS-CoV adaptation determines the minimal infectious dose required to achieve severe respiratory disease.

Keywords

Coronavirus, MERS-CoV, Middle East respiratory syndrome, Respiratory disease, Acute respiratory distress syndrome, Spike protein