Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

Toll-like receptors (TLRs) belong to a powerful system for the recognition and elimination of pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and other pathogens

Influenza viruses (IV) continue to pose an imminent threat to human welfare. Yearly re-occurring seasonal epidemic outbreaks and pandemics with high mortality can occur. Besides vaccination against a limited number of viral strains only a few antiviral drugs are available, which are losing their effectiveness as more and more IV strains become resistant. Thus, new antiviral approaches that omit IV resistance are urgently needed. Here, the dependency on the cellular Raf/MEK/ERK signaling pathway for IV replication opens a new perspective. In consequence, we studied the antiviral potential of the MEK inhibitor Cl-1040 (PD184352). We show that Cl-1040 significantly reduces virus titers in vitro via retention of viral RNP complexes in the cell nucleus. Furthermore, Cl-1040 is effective against a broad range of IV strains, including highly pathogenic avian IV, as well as against a Tamiflu®-resistant IV strain. Using a mouse model, we demonstrate that Cl-1040 can reduce IV lung titers in vivo. Importantly, the treatment window for Cl-1040 expands up to 48 h post infection when Tamiflu® treatment has no effect. In conclusion, Cl-1040 offers an interesting perspective for anti-IV approaches.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic effects daily dental work. Therefore, infection control measures are necessary to prevent infection of dental personnel during dental treatments. The use of a preprocedural mouth rinse with chlorhexidine (CHX), cetylpyridinium chloride (CPC), or hydrogen peroxide (H₂O₂) solution for 30–60 s may reduce the viral load and may protect the personnel in a dental practice. In the present study the virucidal effect of the mouth rinsing solutions ViruProX^® with 0.05% CPC and 1.5% H₂O₂ and BacterX^® pro containing 0.1% CHX, 0.05% CPC, and 0.005% sodium fluoride (F^-) was investigated in vitro. The mouth rinsing solutions successfully inactivated infectious SARS-CoV-2 particles, the causative agent of coronavirus disease 2019 (COVID-19), within 30 s. To determine the effective components, CHX, CPC, H₂O₂, and a combination of CHX and CPC, were tested against SARS-CoV-2 in addition. While a combination of CPC and CHX as well as CPC alone led to a significant reduction of infectious viral particles, H₂O₂ and CHX alone had no virucidal effect against SARS-CoV-2. It can be assumed that preprocedural rinsing of the mouth with ViruProX^® or BacterX^® pro will reduce the viral load in the oral cavity and could thus lower the transmission of SARS-CoV-2 in dental practice.

Antiviral therapies against influenza are required, especially for high-risk patients, severe influenza and in case of highly pathogenic influenza virus (IV) strains. However, currently, licensed drugs that target the virus directly are not very effective and often lead to the development of resistant IV variants. This may be overcome by targeting host cell factors that are required for IV propagation. IV induces a variety of host cell signaling cascades, such as the Raf/MEK/ERK kinase pathway. The activation of this pathway is necessary for IV propagation. MEK-inhibitors block the activation of the pathway on the bottleneck of the signaling cascade leading to impaired virus propagation. In the present study, we aimed to compare the antiviral potency and bioavailability of the MEK-inhibitor CI-1040 versus its major active metabolite ATR-002, in vitro as well as in the mouse model. In cell culture assays, an approximately 10-fold higher concentration of ATR-002 is required to generate the same antiviral activity as for CI-1040. Interestingly, we observed that considerably lower concentrations of ATR-002 were required to achieve a reduction of the viral load in vivo. Pharmacokinetic studies with ATR-002 and CI-1040 in mice have found the Cmax and AUC to be far higher for ATR-002 than for CI-1040. Our results thereby demonstrate the in vivo superiority of the active metabolite ATR-002 over CI-1040 as an antiviral agent despite its weaker cell membrane permeability. Therefore, ATR-002 is an attractive candidate for development as an efficient antiviral agent, especially given the fact that a treatment based on cellular pathway inhibition would be far less likely to lead to viral drug resistance.