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Host directed therapies: COVID-19 and beyond.

ABSTRACT: The global spread of SARS-CoV-2 has necessitated the development of novel, safe and effective therapeutic agents against this virus to stop the pandemic, however the development of novel antivirals may take years, hence, the best alternative available, is to repurpose the existing antiviral drugs with known safety profile in humans. After more than one year into this pandemic, global efforts have yielded the fruits and with the launch of many vaccines in the market, the world is inching towards the end of this pandemic, nonetheless, future pandemics of this magnitude or even greater cannot be denied. The preparedness against viruses of unknown origin should be maintained and the broad-spectrum antivirals with activity against range of viruses should be developed to curb future viral pandemics. The majority of antivirals developed till date are pathogen specific agents, which target critical viral pathways and lack broad spectrum activity required to target wide range of viruses. The surge in drug resistance among pathogens has rendered a compelling need to shift our focus towards host directed factors in the treatment of infectious diseases. This gains special relevance in the case of viral infections, where the pathogen encodes a handful of genes and predominantly depends on host factors for their propagation and persistence. Therefore, future antiviral drug development should focus more on targeting molecules of host pathways that are often hijacked by many viruses. Such cellular proteins of host pathways offer attractive targets for the development of broad-spectrum anticipatory antivirals. In the present article, we have reviewed the host directed therapies (HDTs) effective against viral infections with a special focus on COVID-19. This article also discusses the strategies involved in identifying novel host targets and subsequent development of broad spectrum HDTs.

SUBMITTER: Tripathi D

PROVIDER: S-EPMC8464038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon ? -1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

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Host directed therapies: COVID-19 and beyond.

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