Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses

Figures

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  Figure 1. Chemical structures of cardenolide ouabain (1), bufadienolide bufalin (2), digitoxigenin (3) and its derivative rostafuroxin (4), digoxin (5), oleandrin (6), lanatoside C (7), strophanthidin (8), digitoxin (9), convallatoxin (10), digoxigenin (11), cinobufagin (12), a semisynthetic cardenolide RIDK-34 (13), glucoevatromonoside (14), evomonoside (15), C10 (16), and C11 (17). Compound 1 has a five-membered lactone ring (in red) and compound 2 has a six-membered lactone ring (in blue).

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  Figure 2. The life cycle of non-enveloped DNA and enveloped RNA viruses excluding retroviruses. (1) Life cycle of non-enveloped DNA viruses: a virus attaches to a specific cell surface receptor and enters the host cell. Subsequently, the virus exposes its DNA, which is transported to the cell nucleus and is replicated. Next, the DNA is transcribed into RNA followed by translation to viral proteins, which are then post-transcriptionally modified. The viral proteins and replicated DNA assemble into novel viral particles, which are then released from the host cells via disruption of the cell plasma membrane. (2) Life cycle of enveloped RNA viruses: a virus attaches to a specific cell surface receptor and enters the host cell (not indicated in the scheme) or inserts the RNA through the plasma membrane (indicated). This RNA is replicated via viral RNA synthetase and viral proteins are translated and post-transcriptionally modified. Next, the viral particles are released via exocytosis and are enveloped by the plasma membrane containing glycoproteins on its surface.

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  Figure 3. Molecular pathways triggered by binding of cardiac glycosides (CGs) to the α-subunit of Na+/K+-ATPase (NKA), which are involved in blocking the viral entry into host cells. By CG binding to NKA, conformational changes of its α-subunit trigger non-receptor tyrosine kinase (Src) to phosphorylate the epidermal growth factor receptor (EGFR). This leads to activation of Src homology 2 domain-containing transforming protein (Shc)/growth factor receptor-bound protein 2 (Grb2)/son of sevenless protein (Sos)/rat sarcoma protein (Ras) pathway. Ras further activates the serine/threonine kinase (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, which triggers reactive oxygen species (ROS) production activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and thereby affects the expression of genes in the nucleus and cell proliferation. The cell proliferation is affected also by protein kinase C (PKC), which activates transcription factors, such as AP1. PKC itself is activated either via the Ras/Raf/MEK/ERK pathway or by Ca2+ ions. The levels of Ca2+ can be elevated by another NKA-based pathway, the phospholipase…

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  Figure 4. The effect of cardiac glycosides (CGs) on viral RNA synthesis and processing, and protein translation. CGs block RNA splicing by further unexplained mechanisms, which are likely linked to the Na+/K+-ATPase (NKA) signaling function (not indicated in the scheme). The result of this is a decreased pool of viral messenger ribonucleic acids (mRNAs) and a subsequent block of viral protein synthesis. The translation of viral proteins is hampered also by blocking the pumping function of NKA. As a consequence of this, the intracellular level of K+ ions is decreased, which negatively affects ribosomal function. K+ ions play a physiologically important role in the stabilization of the ribosomal complex. The improper function of ribosomes caused by K+ depletion leads to decreased translation of viral proteins.