Advances in Antiviral Therapies Targeting Toll-like Receptors

ABSTRACT

Introduction: Organisms have evolved a rapid and non-specific way to defend themselves via Toll-like receptors (TLRs), which recognize specific signatures present on invading microbes and viruses. Once detected, these receptors flood the cell with cytokines and IFNs that not only help to eradicate the invading viruses but also activate the adaptive immune response. Owing to difficulties in viral detection, a whole class of TLRs is dedicated to sensing viral nucleic acids, while other TLRs detect viral coat proteins and aid in establishing antiviral immunity. To protect humans better, TLRs and their downstream mediators can be used as potential drug targets, which can be either activated or inhibited, to counter viral infections.

Areas covered: The current review focuses on TLR-targeting investigational drugs developed to treat viral diseases and virus-induced complications.

Expert opinion: TLRs are a good choice for eradicating viral infections because they can fine-tune the immune response. However, TLRs should be exploited carefully, as there have been instances where their activation has led to unwanted responses in terms of both immune and viral activation. Therefore, more focus should be placed on novel drugs that can induce significant and long-term immunity, while concomitantly alleviating side effects.

KEYWORDS:

• Toll-like receptor
• viral infection
• ligand
• clinical trial
• nucleic acid

Article highlights

• Viral invasion triggers a multitude of PRRs involving the TLR family to mount an effective, coordinated, and highly organized reaction, leading to a balanced response to counteract a viral challenge through innate and adaptive immunity.

• Besides mounting an effective antiviral response by activating PRRs, viruses adopt different strategies to attenuate their detection by masking themselves or enhancing the degradation of mediator molecules.

• A deeper understanding of the virus–TLR interaction has generated a wealth of information that has been effectively used to limit viral infections.

• TLRs induce an antiviral mechanism to restrict the viral disease, and the same effect can be achieved by employing a TLR agonist, for example, in cases where viruses have hampered the normal functioning of TLRs.

• In some cases, viral infection exploits TLR signaling for their own benefit. This necessitates the negative regulation of TLRs to counter viral pathogenesis.

Novel drugs that target TLRs are necessary to improve the management of viral diseases, since the clinical evaluation of many drugs has been terminated early owing to non-specific effects and safety concerns.

Financial and competing interests disclosure

This work was supported via S Choi by the Mid-Career Researcher Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (NRF-2015R1A2A2A09001059), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C1992). This work was also supported via S Choi by a grant from the Priority Research Centers Program (NRF 2012-0006687). 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.