Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors:
starting with nicotinamide?
Abstract
COVID-19 patients in China exhibit a proinflammatory environment that is
stronger in severe cases requiring intensive care. 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
a variety of coronaviruses, including COVID-19 and, as it regulates PARP
gene expression, the latter is likely to be activated in COVID-19. 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, which leads to cell
death mainly by depleting NAD+ and ATP, 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
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. Its unique biochemical 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.