Class A G Protein-Coupled Receptor Antagonist Famotidine as a Therapeutic Alternative against SARS-CoV2: An In Silico Analysis

Abstract

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine’s pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.

Histamine receptors and COVID-19

“…The nucleocapsids assembled from gRNA encapsidated by N protein and the structural proteins S, E and M inserted in the endoplasmic reticulum move along the secretory pathway (➐) and form mature virions that are transported to the cell surface in vesicles (➑) and released from the infected cell by exocytosis (➒) [7,10,11]. Bold arrows indicate the sites of action of the histamine H 2 receptor antagonist famotidine as proposed by computational studies [5,36,40], yet not experimentally confirmed [43,51] the investigational nucleotide analog remdesivir that has shown broad antiviral activity and is under clinical evaluation for the treatment of COVID-19 [13,14]. De novo drug development, drug repurposing and natural product screening are also directed at the essential proteases for viral replication [5], PL pro [6,15] and 3CL pro , which cleaves itself and, by cleaving pp1ab at 11 canonical sites (between nsps), it generates nsp4-16 and mediates their maturation [16].…”

“…Furthermore, another in silico molecular docking analysis indicated that the non-specific low-affinity binding of famotidine to the proteases involved in SARS-CoV-2 replication and its interaction with the human host TMPRSS2 (Fig. 1) could be related to the chemical structure of the compound [40]. On the other hand, considering the yet elusive implication of the H 2 receptor in histamine signalling in immunoregulation and inflammation [41,42], the benefit of famotidine in managing the inflammatory and/ or the immune response during the SARS-CoV-2 infection, including the likely automodulation of mast cell activation [43], cannot be excluded at the moment.…”

Union is strength: antiviral and anti-inflammatory drugs for COVID-19

“…Famotidine is an H2 antagonist and antiulcer agent with an optimal safety profile. In silico studies 66 , 67 revealed famotidine as a potential therapeutic agent against SARS-CoV-2 M pro 65 , 66 . Another study indicated that its effect is not the result of antiviral activity, but an anti-inflammatory action.…”

The Pathophysiology, Diagnosis and Treatment of Corona Virus Disease 2019 (COVID-19)

“…Three polyphenols (epigallocatechin gallate, epicatechingallate and gallocatechin-3-gallate) of green tea [80] and compounds from Curcuma longa L. (Zingiberaceae family) [81] interact strongly with one or both catalytic residues (His41 and Cys145) of Mpro, and are considered as potential inhibitors against SARS CoV-2 Mpro. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux, is reported to interact within the catalytic site of the three proteases associated with SARS-CoV2 replication [82].…”