Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets

Abstract

COVID-19 is the name of the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that occurred in 2019. The virus-host-specific interactions, molecular targets on host cell deaths, and the involved signaling are crucial issues, which become potential targets for treatment. Spike protein, angiotensin-converting enzyme 2 (ACE2), cathepsin L-cysteine peptidase, transmembrane protease serine 2 (TMPRSS2), nonstructural protein 1 (Nsp1), open reading frame 7a (ORF7a), viral main protease (3C-like protease (3CLpro) or Mpro), RNA dependent RNA polymerase (RdRp) (Nsp12), non-structural protein 13 (Nsp13) helicase, and papain-like proteinase (PLpro) are molecules associated with SARS-CoV infection and propagation. SARS-CoV-2 can induce host cell death via five kinds of regulated cell death, i.e., apoptosis, necroptosis, pyroptosis, autophagy, and PANoptosis. The mechanisms of these cell deaths are well established and can be disrupted by synthetic small molecules or natural products. There are a variety of compounds proven to play roles in the cell death inhibition, such as pan-caspase inhibitor (z-VAD-fmk) for apoptosis, necrostatin-1 for necroptosis, MCC950, a potent and specific inhibitor of the NLRP3 inflammasome in pyroptosis, and chloroquine/hydroxychloroquine, which can mitigate the corresponding cell death pathways. However, NF-κB signaling is another critical anti-apoptotic or survival route mediated by SARS-CoV-2. Such signaling promotes viral survival, proliferation, and inflammation by inducing the expression of apoptosis inhibitors such as Bcl-2 and XIAP, as well as cytokines, e.g., TNF. As a result, tiny natural compounds functioning as proteasome inhibitors such as celastrol and curcumin can be used to modify NF-κB signaling, providing a responsible method for treating SARS-CoV-2-infected patients. The natural constituents that aid in inhibiting viral infection, progression, and amplification of coronaviruses are also emphasized, which are in the groups of alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones. Natural constituents derived from medicinal herbs have anti-inflammatory and antiviral properties, as well as inhibitory effects, on the viral life cycle, including viral entry, replication, assembly, and release of COVID-19 virions. The phytochemicals contain a high potential for COVID-19 treatment. As a result, SARS-CoV-2-infected cell death processes and signaling might be of high efficacy for therapeutic targeting effects and yielding encouraging outcomes.

Keywords: COVID-19; SARS-CoV-2; cell death; coronavirus; natural compounds; targeted therapy.

Figure 1

A proposed model of SARS-CoV-2-induced apoptosis via both death receptor and mitochondrial pathways. Bid: BH3 interacting-domain death agonist; caspases: cysteine-aspartic proteases; E protein: envelope protein; IFNGR: interferon-gamma receptor; MOMP: mitochondrial outer membrane permeabilization; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; RNA: ribonucleic acid; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; tBid: truncated Bid; TNFR: tumor necrosis factor receptors.

Figure 2

A proposed model of SARS-CoV-2-induced necroptosis. Caspases: cysteine-aspartic proteases; E protein: envelope protein; FADD: Fas-associated via death domain; IFNGR: interferon-gamma receptor; MLKL: mixed lineage kinase domain-like pseudokinase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; RIPK1: receptor-interacting serine/threonine-protein kinase 1; RIPK3: receptor-interacting serine/threonine-protein kinase 3; RNA: ribonucleic acid; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNFR: tumor necrosis factor receptors.

Figure 3

A proposed model of SARS-CoV-2-induced pyroptosis. ASC: apoptosis-associated speck-like protein containing a CARD; Ca²⁺: calcium; E protein: envelope protein; IFNGR: interferon-gamma receptor; K²⁺: potassium; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR family pyrin domain containing 3; ORF3a: open reading frame 3a; RNA: ribonucleic acid; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNFR: tumor necrosis factor receptors; TRAF3: TNFR-associated factor 3; ΔΨm: mitochondrial membrane potential.

Figure 4

A proposed model of SARS-CoV-2-induced autophagy. AKT: serine/threonine kinase 1; E protein: envelope protein; IFNGR: interferon-gamma receptor; LC3-II: the conjugation of LC3 (microtubule-associated protein light chain 3) to phosphatidylethanolamine; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; p62: sequestosome 1 (SQSTM1); PI3K: phosphoinositide 3-kinases; RNA: ribonucleic acid; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TNFR: tumor necrosis factor receptors.