Host-Directed Antiviral Therapy

Abstract

SUMMARY Antiviral drugs have traditionally been developed by directly targeting essential viral components. However, this strategy often fails due to the rapid generation of drug-resistant viruses. Recent genome-wide approaches, such as those employing small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeats (CRISPR) or those using small molecule chemical inhibitors targeting the cellular “kinome,” have been used successfully to identify cellular factors that can support virus replication. Since some of these cellular factors are critical for virus replication, but are dispensable for the host, they can serve as novel targets for antiviral drug development. In addition, potentiation of immune responses, regulation of cytokine storms, and modulation of epigenetic changes upon virus infections are also feasible approaches to control infections. Because it is less likely that viruses will mutate to replace missing cellular functions, the chance of generating drug-resistant mutants with host-targeted inhibitor approaches is minimized. However, drug resistance against some host-directed agents can, in fact, occur under certain circumstances, such as long-term selection pressure of a host-directed antiviral agent that can allow the virus the opportunity to adapt to use an alternate host factor or to alter its affinity toward the target that confers resistance. This review describes novel approaches for antiviral drug development with a focus on host-directed therapies and the potential mechanisms that may account for the acquisition of antiviral drug resistance against host-directed agents.

Emetine as an antiviral agent suppresses SARS-CoV-2 replication by inhibitinginteraction of viral mRNAwith eIF4E: Anin vitrostudy

“…Viruses are well known to exploit several cellular factors to effectively transcribe and translate their genome (Kumar et al, 2020). Like several other viruses, coronaviruses also synthesizetheir protein in cap-dependent manner wherein eIF4E plays a critical role in the initiation of translation (Nakagawa et al, 2016).…”

Baricitinib: A Review of Pharmacology, Safety, and Emerging Clinical Experience in COVID‐19

“…12,13 Antiviral drug discovery has traditionally focused on designing compounds that target essential viral components, including viral proteases or polymerases. 14 This approach has been successful for chronic viral infections, such as HIV and hepatitis C. 15,16 However, direct-acting antivirals are typically narrow in spectrum, take years or even decades to develop, and may have a low barrier to resistance when used as monotherapy. 14 An alternative approach that may be more suitable for emerging viral pathogens is to repurpose approved drugs that target host functions that viruses rely on.…”

“…14 This approach has been successful for chronic viral infections, such as HIV and hepatitis C. 15,16 However, direct-acting antivirals are typically narrow in spectrum, take years or even decades to develop, and may have a low barrier to resistance when used as monotherapy. 14 An alternative approach that may be more suitable for emerging viral pathogens is to repurpose approved drugs that target host functions that viruses rely on. 14 This may drastically reduce the costs and time devoted to early drug discovery and these agents may, in theory, have higher barriers to resistance because most resistance is secondary to mutations in the viral genome.…”

“…14 An alternative approach that may be more suitable for emerging viral pathogens is to repurpose approved drugs that target host functions that viruses rely on. 14 This may drastically reduce the costs and time devoted to early drug discovery and these agents may, in theory, have higher barriers to resistance because most resistance is secondary to mutations in the viral genome. 14 Baricitinib (C 16 H 17 N 7 O 2 S, formerly LY3009104) is a small molecule reversible Janus-associated kinase (JAK)-inhibitor approved in over 65 countries for the treatment of adults with moderate to severe rheumatoid arthritis (RA).…”

“…14 This may drastically reduce the costs and time devoted to early drug discovery and these agents may, in theory, have higher barriers to resistance because most resistance is secondary to mutations in the viral genome. 14 Baricitinib (C 16 H 17 N 7 O 2 S, formerly LY3009104) is a small molecule reversible Janus-associated kinase (JAK)-inhibitor approved in over 65 countries for the treatment of adults with moderate to severe rheumatoid arthritis (RA). 1,5,17 The JAK/signal transducers and activators of transcription (STAT)-pathway mediates the signaling of multiple cytokines and interrupting this pathway may, therefore, be an attractive strategy to modulate the immunopathology seen with SARS-CoV-2 infection.…”