COVID 19, Paxlovid and the lesson from rare genetic diseases with naturally occurring protection from SARS-CoV-2 infection

Impaired ACE2 glycosylation and protease activity in Fabry disease protects from COVID‐19

“…During the COVID‐19 pandemic, a low rate of SARS‐CoV‐2 infection, with mild disease manifestations were reported in FD patients [6]. We also found a low rate of SARS‐CoV‐2 infection upon surveying our cohort of 40 ERT‐treated FD patients, where only one patient tested positive for COVID‐19 with only minor symptoms [7].…”

“…5]. Given our findings in GS/BS patients, we tested whether similar effects might be responsible for them being less prone to SARS‐CoV‐2 infection and severe clinical manifestations of COVID‐19 [6, 7]. This was assessed by measuring the levels of mononuclear ACE2 and its glycosylation alongside plasma Cat‐L activity [Supplementary Methods] in 15 FD patients (10 females, 5 males, age range 25–72 y.o), in 1 patient affected by another LSD, Gaucher disease (55 y.o.)…”

“…As Cat‐L upregulation is a severe enhancer of SARS‐CoV‐2 entry and infection [5], the altered endosomal function‐dependent reduced Cat‐L activity observed in FD patients suggests that S priming can be severely affected, providing an important protective mechanism. Moreover, the altered endosomal processing provides a robust mechanistic rationale for the effects of the combination of nirmatrelvir‐ritonavir (Paxlovid), a new antiviral drug, which exerts its effect via inhibition of proteins involved in lysosomal processes key for SARS‐CoV‐2 cell entry and replication–transcription [7].…”

“…In summary, the findings in FD disease and those coming from our previous study in GS/BS highlight the essential role of endosomal–lysosomal functions in SARS‐CoV‐2 infection. The observed protection from SARS‐CoV‐2 infection in GS/BS patients could be the result of the impaired lysosomal functions due to their chronic metabolic alkalosis and in FD patients the result of impaired lysosomal functions due to the LSD [7]. Moreover, FD and GS/BS patients’ physiology provides an “in vivo ” human model where the effects of endosomal pH, ACE2 glycosylation status, and Cat‐L activity alter SARS‐CoV‐2 infection rate and severity and point to these as targets to fight COVID‐19.…”

Comprehensive Review on the Synthetic Strategies toward Anti-SARS-CoV-2 Drug Ensitrelvir

“…The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious infection that has spread worldwide since 2019 . Although the World Health Organization announced the end of the emergency phase of COVID-19 in May 2023, long COVID still needs more attention, posing an enormous challenge on drug discovery . Remdesivir, molnupiravir, deuremidevir hydrobromide (VV116), azvudine, paxlovid (the combinations of nirmatrelvir and ritonavir), simnotrelvir, and ensitrelvir are approved as small molecular drugs to treat the pneumonia caused by SARS-CoV-2 (Figure ).…”