An overview of the role of Niemann-pick C1 (NPC1) in viral infections and inhibition of viral infections through NPC1 inhibitor

Abstract

Viruses communicate with their hosts through interactions with proteins, lipids, and carbohydrate moieties on the plasma membrane (PM), often resulting in viral absorption via receptor-mediated endocytosis. Many viruses cannot multiply unless the host’s cholesterol level remains steady. The large endo/lysosomal membrane protein (MP) Niemann-Pick C1 (NPC1), which is involved in cellular cholesterol transport, is a crucial intracellular receptor for viral infection. NPC1 is a ubiquitous housekeeping protein essential for the controlled cholesterol efflux from lysosomes. Its human absence results in Niemann-Pick type C disease, a deadly lysosomal storage disorder. NPC1 is a crucial viral receptor and an essential host component for filovirus entrance, infection, and pathogenesis. For filovirus entrance, NPC1’s cellular function is unnecessary. Furthermore, blocking NPC1 limits the entry and replication of the African swine fever virus by disrupting cholesterol homeostasis. Cell entrance of quasi-enveloped variants of hepatitis A virus and hepatitis E virus has also been linked to NPC1. By controlling cholesterol levels, NPC1 is also necessary for the effective release of reovirus cores into the cytoplasm. Drugs that limit NPC1’s activity are effective against several viruses, including SARS-CoV and Type I Feline Coronavirus (F-CoV). These findings reveal NPC1 as a potential therapeutic target for treating viral illnesses and demonstrate its significance for several viral infections. This article provides a synopsis of NPC1’s function in viral infections and a review of NPC1 inhibitors that may be used to counteract viral infections. Graphical Abstract

RETRACTED ARTICLE: Potential use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and prevention method in viral infection

“…Determining viral entry receptors is the principal determinant of host range and tissue tropism. Viruses also utilize cellular lipids and host lipid metabolism to facilitate reproduction and spread [ 85 ]. The host cell and the virus may both have perspectives on cholesterol during a viral infection.…”

“…Nonetheless, the researchers’ findings offer an initial indication of how to investigate this route further. By employing a stable replicon cell line and conducting time-of-addition experiments, it was determined that imipramine hindered the post-fusion viral RNA replication stages and prevented the entrance and/or fusion of retroviral pseudoparticles carrying the chikungunya virus envelope [ 85 – 88 ].…”

More evidence for widespread antagonistic pleiotropy in polymorphic disease alleles

“…Consistent with this, studies using cell lines derived from green monkey and human tissue showed a decrease in the ability of Ebola and Marburg viral analogs to infect cells with SNPs inserted into the NPC1 sequence ( Kondoh et al, 2018 ). Finally, several antiviral drugs work by blocking the NPC1 protein in patients ( Ahmad et al, 2023 ), suggesting that heterozygotes are likely to experience increased resistance to such infections.…”

Cholesterol and COVID-19—therapeutic opportunities at the host/virus interface during cell entry

“…In this review, we described several key roles how cholesterol at the cell surface and in endolysosomes influences the efficacy of SARS-CoV-2 entry, providing opportunities for drugs targeting cholesterol-sensitive mechanism in these locations to reduce SARS-CoV-2 infectivity and COVID-19 disease severity. It would have gone beyond the scope of this review to cover the influence of cholesterol on many other aspects of the viral cycle, such as replication, assembly, and viral release, and we refer the reader to excellent review articles that cover cholesterol-sensitive mechanisms not only during SARS-CoV-2 surface recognition and cell entry but also viral replication, assembly, and release ( Ballout et al, 2020 ; Fecchi et al, 2020 ; Tang et al, 2021b ; Glitscher & Hildt, 2021 ; Palacios-Rapalo et al, 2021 ; Barrantes, 2022 ; Cesar-Silva et al, 2022 ; Kowalska et al, 2022 ; Wang et al, 2022 , 2023 ; Ahmad et al, 2023 ).…”