Viral-Host Dependency Factors as Therapeutic Targets to Overcome Antiviral Drug-Resistance: A Focus on Innate Immune Modulation

Abstract

The development of antiviral drugs, has provided enormous achievements in our recent history in the fight against viral infections. To date, most of the approved antiviral drugs target virus-encoded proteins to achieve direct antiviral activity. Nonetheless, the inherent idiosyncrasy of viral mutations during their replication cycle, enable many viruses to adapt to the new barriers, becoming resistant to therapies, therefore, representing an ever-present menace and prompting the scientific community towards the development of novel therapeutic strategies. Taking advantage of the increasing knowledge of virus-host cell interactions, the targeting of cellular factors or pathways essential for virus survival turns into an alternative strategy to intervene in almost every step of viral replication cycle. Since host factors are evolutionary conserved, viral evasion to host-directed therapies (HDT) would impose a higher genetic barrier to the emergence of resistant strains. Thus, targeting host factors has long been considered an alternative strategy to overcome viral resistance. Nevertheless, targeting host factors or pathways potentially hints undesired off targets effects, and therefore, a critical risk-benefit evaluation is required. The present review discusses the current state-of-the-art on the identification of viral host dependency factors (HDF) and the workflow required for the development of HDT as antivirals. Then, we focus on the feasibility of using a specific class of host factors, those involved in innate immune modulation, as broad-spectrum antiviral therapeutic strategies. Finally, a brief summary of major roadblocks derived from targeting host cellular proteins and putative future strategies to overcome its major limitations is proposed.

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

“…On the other hand, several viruses usurp the same host factors and, therefore, targeting these host functions could lead to the development of broad-spectrum antivirals [ 12 , 81 , 123 , 125 – 128 ]. Nevertheless, to develop host-targeting antivirals, it is necessary to understand the host–virus molecular mechanisms [ 66 , 129 ].…”

“…The host factor that is being targeted needs to be essential for the virus to replicate but not mandatory for host cell functions, risking toxicity and undesired off-target effects. If not finely controlled, inhibition of host factors has the potential to disrupt vital cellular processes since the impairment of numerous host processes is detrimental to the cell [ 35 , 77 , 123 , 124 , 127 – 129 ]. Regardless, in the context of acute EBOV infection, these treatments are required for a relatively short timeframe, which potentially mitigates toxicity and side effects [ 77 ].…”

Japanese Encephalitis Virus: An Emerging Threat in the Indo-Pacific Region

“…Various proteins, crucial for viral attachment, replication and maturation, can be considered as potential drug targets. Data states that developing host-related proteins as drug targets can be more advantageous than targeting the viral proteins, as it allows targeting multiple viruses simultaneously [51]. It reduces the chances of drug resistance and maintains drug affectivity, even if the virus is mutated.…”

Human‐virus protein‐protein interactions maps assist in revealing the pathogenesis of viral infection

“…Viral diseases have threatened humanity throughout history. [1][2][3] From 1800 to 2021, viruses have triggered multiple pandemics outbreaks: 1918-1920, the influenza A virus H1N1 caused a major outbreak of the Spanish flu, killing an estimated 50-100 million people globally 4 ; the human immunodeficiency virus (HIV) that emerged in 1981 is transmitted through body fluids and has claimed more than 36.3 million lives so far (https://aidsinfo.unaids.org); the ongoing highly infectious coronavirus disease 2019 (COVID-19) epidemic had infected over 770 million people and killed more than 6 million worldwide, according to the World Health Organization (WHO) (https://covid19.who.int/). Infectious diseases are responsible for 20% of global mortality, of which about one-third are caused by viral diseases.…”