Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

Abstract

COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is over-expressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and ATP, especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide, which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines, and is effective against HIV infection. These properties qualify nicotinamide for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.

CD38 in the age of COVID-19: a medical perspective

“…Another aspect of NAM effects that is relevant to the metabolome rewiring of NAD 1 is their contribution to maintaining homeostasis through the involvement of gut microbiota in NAD 1 biogenesis (131). NAM suppliers (such as NR and NMN) are thus potential candidates for use in COVID-19 treatment by replenishing NAD 1 levels (45,125,129). NMN plays an anti-inflammatory role in preclinical models decreasing the levels of lactic acidosis and IL-6.…”

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

“…B and T cell-associated USRs were also seen (Figure 4D, green circles) (59–61), consistent with development of an adaptive immune response. A relatively minor PARP1 signature was identified (Figure 4D), with PARP inhibitors being considered for COVID-19 therapy (62, 63). A strong signature associated with estrogen receptor 1 (ESR1) was observed (Figure 4D), with estrogen having anti-inflammatory properties and believed to be associated with reduced COVID-19 severity in women (64–66), and reduced SARS-CoV disease severity in female mice (46, 67).…”

The PARP Way to Epigenetic Changes

“…This upregulation is caused by the aryl hydrocarbon receptor (AhR), which is overexpressed in coronaviruses. The AhR regulates PARP1 gene expression, implying that upregulation of PARP1 is likely to result from coronavirus infection [ 22 ]. Activation of PARP1 leads to cell death by consuming large amounts of NAD + and ATP; this is even more likely to happen during an infected state [ 104 ].…”

“… The wide range of functions carried out by PARP enzymes . Chromatin remodeling: PARylation determines conformational changes of the chromatin [ 3 ]; change in methylation profile: PARP1 neutralize DNMT1 activity [ 20 ]; RNA biology: the promoter RNA (pRNA) mediates association of TIP5 and PARP1 and activates the enzymatic activity of PARP1 to PARylate PARP1 itself, TIP5, or histones [ 21 ]; other cross-talks: depicted few examples of new emerging interactions of PARP1 with some nuclear proteins; response to infection: the consumption of NAD in cells is dramatically increased by the activation of PARP1 during infections (i.e., COVID 19) [ 22 ]. …”