Pathways

Atoltivimab (REGN 3470), Odesivimab (REGN 3471), and Maftivimab are monoclonal antibody (mAb) and part of the product, INMAZEB, containing three monoclonal IgG1K antibodies directed against the GP1 and GP2 glycoprotein of Zaire ebolavirus. INMAZEB, formally known as REGN-EB3, is a combination of Atoltivimab, Odesivimab, and Maftivimab in equimolar proportions. Each of them bind to a distinct portion of the GP1,2 glycoprotein and protect against ebola virus infection.It has not been established as efficacious for an other species within the Ebolavirus or Marburgvirua genera. INMAZEB is produced by Regeneron Pharmaceuticals and was granted FDA approval on October 14, 2020. Ebola virus (Zaire ebolavirus) has been responsible for at least 17 known outbreaks with an average fatality rate of 43.92%. Immune therapy using monoclonal antibodies (mAbs) is used to combat infectious diseases due to its rapid development, low toxicity, and high specificity. Ebola virus particles expose the glycoprotein, which is comprised of a trimer of GP1, and GP2 subunit heterodimers, connected by a disulfide bond, on their surface. Atoltivimab inhibits a distinct portion of the Zaire ebolavirus envelope glycoprotein. This blocks viral endocytosis and infection of the host cells. Atoltivimab exhibits strong (<90%) neutralization of chimeric lentiviral particles expressing Ebola virus.

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a pathway with many functions, one of which is an anti-viral response. IFN-γ activates interferon gamma receptors 1 and 2 (INFGR1 and INFGR2), which are associated with Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) which leads to the phosphorylation of signal transducer and activator of transcription 1 (STAT1) homodimers. Phosphorylated STAT1 homodimers are translocated to the nucleus where it activates the transcription of gamma activated sequence (GAS) elements, which activates an inflammatory response and immunoregulation. INFGR1 and INFGR2 also phosphoylate STAT3 homodimers which are subsequently translocated to the nucleus where they also activate GAS elements. Type 1 interferons (IFNs) activate interferon alpha receptors 1 and 2 (IFNAR1 and IFNAR2) which are associated with tyrosine kinase 2 (TYK2) and JAK1 respectively. This receptor complex also phosphorylates STAT3 homodimers. The IFNAR complex phorphoylates STAT5 which binds with Crk-like protein (CRKL). This complex also activates the GAS elements in the nucleus. The main pathway of IFNAR1 and IFNAR2 is through the phosphorylation of STAT1 and STAT2. Together with interferon regulatory factor (IRF9) they form the interferon-stimulated gene factor 3 (ISGF3). The ISGF3 translocates to the nucleus and initiates the trascription of Interferon-sensitive response element (ISRE). This leads to an antiviral response, immunoregulation, antigen presentation, and checkpoint proteins. THE ISRE genes also activate IFN regulated genes. These along with lipopolysaccharides or foreign pathogens activates interferon Regulatory Factor 7 (IRF7). IRF7 is phosphorylated and bound with nuclear factor kappa B (NFKB). This causes the induction of type 1 INFs, which further activates the pathway. IFNAR1 and IFNAR2, activated by type 1 IFNs, signal through TYK2 and JAK1 to also trigger the activation of the NFKB pathway through phosphorylated STAT3, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs). They act through IKKa and IKKb to drive NFKB induction of genes associated with survival signals, antigen processing and presentation, and proliferation. Cytokines, like the various interleukins, activate their corresponding cytokine receptors/JAK complexes. This results in the phosphorylation of STATs, such as STAT3 and STAT5 or a STAT3 homodimer. These phosphorylated STATs are translocated to the nucleus where they transcribe genes involved in inflammation, angiogenesis, proliferation, and survival.

Rimantadine is an RNA synthesis inhibitor used to prevent influenza A infection.The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. It may play a role in the inhibition of the matrix protein 2 protein which is required for the uncoating of the protein. The inhibition of matrix protein 2 prevents the virus from replicating and further infecting cells.

Peginterferon alfa-2a is a modified form of recombinant human interferon, which is used to activate interferon alpha receptors in the JAK-STAT pathway. This is used to stimulate the innate antiviral response in the treatment of hepatitis B and C viruses. Peginterferon alfa-2a activate interferon alpha receptors 1 and 2 (IFNAR1 and IFNAR2) which are associated with tyrosine kinase 2 (TYK2) and JAK1 respectively. This receptor complex also phosphorylates STAT3 homodimers. The IFNAR complex phorphoylates STAT5 which binds with Crk-like protein (CRKL). This activates the transcription of gamma activated sequence (GAS) elements, which activates an inflammatory response and immunoregulation. The main pathway of IFNAR1 and IFNAR2 is through the phosphorylation of STAT1 and STAT2. Together with interferon regulatory factor (IRF9) they form the interferon-stimulated gene factor 3 (ISGF3). The ISGF3 translocates to the nucleus and initiates the trascription of Interferon-sensitive response element (ISRE). This leads to an antiviral response, immunoregulation, antigen presentation, and checkpoint proteins. THE ISRE genes also activate IFN regulated genes. These along with lipopolysaccharides or foreign pathogens activates interferon Regulatory Factor 7 (IRF7). IRF7 is phosphorylated and bound with nuclear factor kappa B (NFKB). This causes the induction of type 1 INFs, which further activates the pathway. IFNAR1 and IFNAR2 signal through TYK2 and JAK1 to also trigger the activation of the NFKB pathway through phosphorylated STAT3, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs). They act through IKKa and IKKb to drive NFKB induction of genes associated with survival signals, antigen processing and presentation, and proliferation.

Oseltamivir is a pro-drug neuraminidase inhibitor used in the prophylaxis and treatment of influenza A (including pandemic H1N1) and B. Oseltamivir is extensively converted to the active metabolite oseltamivir caboxylate, by liver esterases. Viral neuraminidase enzymes are glycoproteins found on the virion surface which are important in the viral release from infected cells in order to further spread the virus in the body. Viral Neuraminidase helps viruses to be released from the plasma membrane of the host cell after budding by cleaving terminal sialic acid resides from glycan structures on the surface of the infected cell. It is also important in viral entry into uninfected cells. Both the inhibition of entry and release reduces viral shedding and infectivity.

Favipiravir is a modified pyrazine analog pro-drug that is used to manage influenza A and B with the potential to target other viral infections. Favipiravirmay be an alternative option for influenza strains that are resistant to neuramidase inhibitors. It has been investigated for the treatment of Ebola virus, Lassa virus, and COVID-19. Favipiravir is a prodrug that undergoes ribosylation and phosphorylation by host enzymes to synthesis Favipiravir-RTP. Favirpiravir-RTP binds to and inhibits RNA dependent RNA polymerase (RdRp). The inhibition of RdRp prevents viral transcription and replication. Some students have found that favipiravir-RTP is incorporated into a nascent RNA strans and prevents RNA strand elongation and viral proliferation. Studies have also found that the presence of purine analogs reduces the activity of favipiravir-RTP's antiviral activity, which suggests competition between favipiravir-RTP and purine nucleosides for RdRp binding.

Maraviroc, known by the brand name Selzentry or Celsentri, is a chemokine receptor antagonist drug used to treat HIV-1 infections. It was developed by the drug company Pfizer. Maraviroc blocks HIV entry to the host cell by selectively binding to the human chemokine receptor (CCR5) present on the membrane of CD4 cells (T cells). This prevents the interaction of HIV-1 gp120 and CCR5 which is necessary for HIV to enter the cell and replicate.

Baloxavir marboxil is a polymerase acidic endonuclease inhibitor used to treat uncomplicated influenza A, B, and Avian. It is specifically a first-in-class cap-dependent endonuclease inhibitor. It is a prodrug of baloxavir with an improved absorption profile than its active metabolite due to the addition of a phenolic hydroxyl group to its structure. Influenza virus RNA polymerase is made up of three subunits: polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), and polymerase acidic protein (PA). The PB2 subunit binds to the cap of host cellular pre-messenger RNA, which allows the polymerase acidic protein to cleave the capped pre-messenger RNA.This is the initial step of mRNA synthesis so viral mRNA transcription can occur. After administration, the prodrug baloxavir marboxil is almost completely hydrolyzed by esterases in the gastrointestinal lumen, intestinal epithelium, liver and blood to its active metabolite, baloxavir. Balaxovir selectively inhibits the polymerase acidic protein, which blocks the initiation of mRNA synthesis which prevents influenza virus proliferation.

Palivizumab is a monoclonal anti respiratory syncytial virus (RSV) F protein antibody used to prevent serious sequelae caused by RSV infection in pediatric patients. It is produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of RSV. Palivizumab binds to the fusion glycoprotein F of RSV which inhibits the binding and uptake of the virus into host cells. This prevents viral propagation and infection.