Novel drug discovery approaches for treating arenavirus infections

ABSTRACT

Introduction: Arenaviruses are enveloped negative stranded viruses endemic in Africa, Europe and the Americas. Several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. So far, there are no FDA-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. The major human pathogenic arenaviruses are classified as Category A agents and require biosafety level (BSL)-4 containment.

Areas covered: Herein, the authors cover the recent progress in the development of BSL2 surrogate systems that recapitulate the entire or specific steps of the arenavirus life cycle and are serving as powerful platforms for drug discovery. Furthermore, they highlight the identification of selected novel drugs that target individual steps of arenavirus multiplication describing their discovery, their targets, and mode of action.

Expert opinion: The lack of effective drugs against arenaviruses is an unmatched challenge in current medical virology. Novel technologies have provided important insights into the basic biology of arenaviruses and the mechanisms underlying virus-host cell interaction. Significant progress of our understanding of how the virus invades the host cell paved the way to develop powerful novel screening platforms. Recent efforts have provided a range of promising drug candidates currently under evaluation for therapeutic intervention in vivo.

KEYWORDS:

• Arenavirus
• LASV
• LCMV
• antiviral
• high throughput screening
• sensor
• SKI-1/S1P
• envelope glycoprotein

Article Highlights

• Arenaviruses are enveloped negative stranded viruses that can cause severe viral hemorrhagic fevers in humans with high mortality and limited therapeutic options.

• The major human pathogenic arenaviruses require biosafety level (BSL)-4 and -3 containment. BSL2 surrogate systems recapitulate specific steps of the arenavirus life cycle and are powerful platforms for drug discovery.

• Several small molecules (ST-193, ST-193, 17C8) interfere with virus-cell fusion that represents an “Achilles heel” for arenaviruses.

• Targeting viral replication and transcription is a promising approach to limit arenavirus spread (Ribavirin, Favipiravir (T-705), peptide-conjugated morpholino oligomers and the pyrimidine biosynthesis inhibitor A).

• The GPC processing mediated by the cellular proprotein convertase SKI-1/S1P is a powerful drug target (e.g. PF-429242).

• Interference with the matrix protein Z leads to significant arenavirus egress inhibition (e.g. valproic acid).

• The cell-based nature of the BSL2 surrogate systems assays allows targeting of viral and cellular factors, as well as interactions between them.This box summarizes key points contained in the article.

Financial and Competing Interests Disclosure

This work was supported by the Swiss National Science Foundation grant FN 310030-149746 (to S Kunz) and funds from the University of Lausanne (to S Kunz). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.