An overview on small molecules acting as broad-spectrum agents for yellow fever infection

ABSTRACT

Introduction

Yellow fever virus (YFV) is a mosquito-borne flavivirus, endemic in 47 countries in Africa and South America, which causes febrile symptoms that can evolve in 15% of the patients to serious hemorrhagic conditions, liver injury, and multiorgan failure. Although a highly effective vaccine (YF-17D vaccine) is available, to date, no antiviral drugs have been approved for the prevention and treatment of YFV infections.

Areas covered

This review article focuses on the description of viral targets that have been considered within YFV and flavivirus drug discovery studies and on the most relevant candidates reported so far that elicit broad-spectrum inhibition against relevant strains and mutants of YFV.

Expert opinion

Considering the growing interest on (re)emerging vector-borne viral infections, it is expected that flavivirus drug discovery will quickly deliver potential candidates for clinical evaluation. Due to similarity among flaviviral targets, several candidates identified against different flaviviruses have shown broad-spectrum activity, thus exhibiting anti-YFV activity, as well. In this regard, it would be desirable to routinely include the assessment of antiviral activity against different YFV strains. On the other hand, the development of host targeting agents are still at an initial stage and deserve further focused efforts.

KEYWORDS:

• Yellow fever virus
• antiviral drug
• Flavivirus
• NS3
• NS5
• medicinal chemistry
• broad-spectrum agents

Article highlights

• The traditional viral proteins, mainly NS3 protease and NS5 RNA-dependent RNA polymerase, represent the major targets for developing new antiviral therapeutics against YFV.

• Novel viral targets are emerging such as the NS4B protein, i.e. a non-structural virus protein without any known enzymatic function.

• An effective anti-YFV agent should have a broad-spectrum activity against other members of Flavivirus genus, which could establish co-infections in the same individual.

• Considering the structural similarity among flaviviruses viral targets, flaviviruses drug candidates show the potential to be broad-spectrum anti-flavivirus agents.

• Most of the anti-YFV agents have not been identified by specific studies but within projects focused on the identification of antiviral agents against different members of Flavivirus genus.

• The increasing antiviral drug discovery efforts will provide new broad-spectrum agents against YFV with known or innovative mode of action

Abbreviations

Β-OG, β-N-octyl-glucoside; C, capsid; CC₅₀, concentration that reduces the cell viability by 50%; CFI, cell-based flavivirus infection; CPE, cytopathic effect; DC-SIGN, dendritic cell-specific ICAM3-grabbing nonintegrin; DENV, dengue virus; DMPK, drug metabolism and PK; E, envelope; EC₅₀, half maximal effective concentration; ER, endoplasmic reticulum; HTS, high-throughput screening; IC₅₀, half-maximal inhibitory concentration; ICAM3, intercellular adhesion molecule-3; i.p., intraperitoneal; i.v., intravenous; L-SIGN, liver/limphnode-specific ICAM3 grabbing nonintegrin; Hsp, heat-shock proteins; Ifit1, IFN-induced RNA-binding protein; JEV, Japanese encephalitis virus; M, membrane; MTase, methyltransferase; NI, nucleoside/nucleotide inhibitor; NNI, non-nucleoside/nucleotide inhibitor; NS, non-structural protein; p.o., per os; PK, pharmacokinetic; POWV, Powassan virus; PRA, plaque reduction assay; RC, replication complex; qRT-PCR, real-time quantitative polymerase chain reaction; RdRp, RNA-dependent RNA polymerase; RNAi, RNA interference; RTPase, RNA 5’-triphosphatase; ss, single-strand; SAM, S-adenosylmethionine; SAR, structure–activity relationship; SI, selectivity index; TBEV, Tick-Borne Encephalitis Virus; UTR, untranslated region; VYR, virus yield reduction; YF, yellow fever; YFV, yellow fever virus; WNV, West-Nile virus; ZIKV, Zika virus.

Declaration of Interest

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

T Felicetti was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca-MIUR - PRIN 2017 - cod. 2017BMK8JR. Meanwhile, R Cannalire was supported by the MIUR-Ministero dell’Istruzione, dell’Università e della Ricerca (Italian Ministry of Education, University and Research), PON R&I 2014-2020-AIM (Attraction and International Mobility), project AIM1873131 - Num. Attività 2 - Linea 2.1.