Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Abstract

Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

In vitro interaction of potential antiviral TMPRSS2 inhibitors with human serum albumin and cytochrome P 450 isoenzymes

“…In previous studies, human lung epithelium-derived Calu-3 cells infected with H1N1 or H3N2 influenza viruses were treated with MI-432 and related potential TMPRSS2 inhibitors at a concentration of 50 μM. After 48 h, significantly reduced viral titers were observed when compared to controls in absence of inhibitors [24] , [34] . Furthermore, it has been recently demonstrated that the inhibitors MI-432 and MI-1900 prevented the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells in a dose-dependent manner, most-likely via an inhibition of the membrane-bound host protease TMPRSS2 [2] .…”

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

“…Currently, there are only few approved therapeutic options with limited efficacies in the treatment of acute influenza virus infections, including administration of M2 ion channel blockers or neuraminidase inhibitors 21 . Very recently, the pyrazinecarboxamide RNA polymerase inhibitor, favipiravir was approved in Japan against influenza 22 .…”

Peptidomimetic furin inhibitor MI-701 in combination with oseltamivir and ribavirin efficiently blocks propagation of highly pathogenic avian influenza viruses and delays high level oseltamivir resistance in MDCK cells

“…503 However, before any medication with furin inhibitors will be 504 considered for use as antivirals, pharmacokinetics and pharmacol-505 ogy studies in animals need to be performed to clarify the absorp- Dunning et al, 2014;Tarbet et al, 2012Tarbet et al, , 2014 534 Webster and Govorkova, 2014). 535 Other cellular proteins involved in influenza virus replication 536 can also be exploited as targets for a combination drug therapy 537 (Steinmetzer et al, 2015). For instance, blockage of Raf/MEK/ERK, 538 NFjB, PI3K/Akt/mTOR and PKC pathways by kinase inhibitors 539 interfered with virus production (Ludwig et al, 2014;Planz, Fig.…”