Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus

McGowan, David; Herschke, Florence; Pauwels, Frederik; Stoops, Bart; Pieters, Serge; Scholliers, Annick; Thoné, Tine; Schoubroeck, Bertrand Van; Pooter, Dorien De; Mostmans, Wendy; Khamlichi, Mourad Daoubi; Embrechts, Werner; Dhuyvetter, Deborah; Smyej, Ilham; Arnoult, Éric; Demin, Samuël; Borghys, Herman; Fanning, Gregory; Vlach, Jaromir; Raboisson, Pierre

doi:10.1021/acs.jmedchem.6b00747

Cited by 35 publications

(37 citation statements)

References 40 publications

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“…Using WBP-1 and BALB/c mice, we demonstrated that the antiviral compound R848 (Resiquimod) can be used to effectively treat SARS-CoV-2 infection. As a dual TLR7/TLR8 agonist, R848 is used as a drug to help treat topical viral infections, tumors and asthma, or as an adjuvant to increase the effective of vaccines [48]. The activation of Toll-like receptors triggers a signaling cascade that leads to the production of interferon-stimulated genes and proinflammatory cytokines with antiviral activities.…”

Section: Discussionmentioning

confidence: 99%

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

et al. 2021

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Background: An ideal animal model to study SARS-coronavirus 2 (SARS-CoV-2) pathogenesis and evaluate therapies and vaccines should reproduce SARS-CoV-2 infection and recapitulate lung disease like those seen in humans. The angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS-CoV-2, but mice are resistant to the infection because their ACE2 is incompatible with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein .Methods: SARS-CoV-2 was passaged in BALB/c mice to obtain mouse-adapted virus strain. Complete genome deep sequencing of different generations of viruses was performed to characterize the dynamics of the adaptive mutations in SARS-CoV-2. Indirect immunofluorescence analysis and Biolayer interferometry experiments determined the binding affinity of mouse-adapted SARS-CoV-2 WBP-1 RBD to mouse ACE2 and human ACE2. Finally, we tested whether TLR7/8 agonist Resiquimod (R848) could also inhibit the replication of WBP-1 in the mouse model. Findings: The mouse-adapted strain WBP-1 showed increased infectivity in BALB/c mice and led to severe interstitial pneumonia. We characterized the dynamics of the adaptive mutations in SARS-CoV-2 and demonstrated that Q493K and Q498H in RBD significantly increased its binding affinity towards mouse ACE2. Additionally, the study tentatively found that the TLR7/8 agonist Resiquimod was able to protect mice against WBP-1 challenge. Therefore, this mouse-adapted strain is a useful tool to investigate COVID-19 and develop new therapies. Interpretation: We found for the first time that the Q493K and Q498H mutations in the RBD of WBP-1 enhanced its interactive affinities with mACE2. The mouse-adapted SARS-CoV-2 provides a valuable tool for the evaluation of novel antiviral and vaccine strategies. This study also tentatively verified the antiviral activity of TLR7/8 agonist Resiquimod against SARS-CoV-2 in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

et al. 2021

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“…The same compound also caused no significant HBsAg decline in combination with tenofovir in treatment-naïve patients [ 156 ]. Pyrimidine analogues were recently identified as potent dual TLR7/8 modulators ( Figure 6 ii) [ 157 ]. Structural modifications led to novel 2,4-diaminoquinazoline dual TLR7/8 agonists with increased potency and proved that changing the stereochemistry in one single stereocenter leads to TLR8 selectivity ( Figure 6 iii) [ 158 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

“… Innate immunity modulators; ( i ) Selective TLR7 agonist [ 163 ] ( ii ) TLR7/8 dual agonist [ 157 ] ( iii ) Dual TLR7/8 agonist. (R) isomer results in selective TLR8 agonist [ 158 ] ( iv ) Selective TLR8 agonist [ 159 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Recent Advances in Hepatitis B Treatment

et al. 2021

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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“…Resiquimod (R848), the synthetic dual agonist of hTLR7/8, has been proven effective for genital herpes treatment (Kanzler, Barrat, Hessel, & Coffman, ). Subsequently, a series of imidazo‐quinazolines, thiazolo‐quinolines, furo‐quinolines, and more recent furo‐pyridines and amino‐imidazoles analogues have been discovered as potential hTLR8 agonists (Figure a) (Beesu et al, , ; Kokatla et al, ; McGowan et al, ; Salunke et al, ; Yoo et al, ). The hTLR8 antagonists currently under development are structural analogue of agonists, for example, 3H imidazoquinolines for TLR7/8 dual antagonists(Shukla, Malladi, Day, & David, ), pyrazolo[1,5‐ a ]pyrimidine derivatives and quinoline derivatives as hTLR8 antagonists (Figure b) (Zhang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Subtle differences in chemical pattern between human toll‐like receptor 8 agonists and antagonists: Emerging chemical patterns analysis

et al. 2019

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Due to the potencies in the treatments of cancer, infectious diseases, and autoimmune diseases, the developments of human TLR8 (hTLR8) agonists and antagonists have attracted widespread attentions. The hTLR8 agonists and antagonists have similar structures but with completely opposite biological effects. Up to date, the subtle differences in the structures between the hTLR8 agonists and antagonists are still unknown. In this work, emerging chemical pattern (ECP) was successfully used to extract the key chemical patterns of the hTLR8 agonists and antagonists. By using CAEP classifier, an optimal ECP model with only 3 descriptors was established with the overall prediction accuracy larger than 90%. Further hierarchical cluster analysis and molecular docking showed that the H-bond and hydrophobic properties are the key features distinguishing the hTLR8 agonists from antagonists. Comparing with the antagonists, the agonists show stronger specific H-bond properties, while antagonists have stronger non-specific hydrophobic properties. The significant differences in the structural properties may be closely related to the activation/inhibition mechanism of hTLR8. K E Y W O R D Sagonist, antagonist, emerging chemical pattern, prediction, toll-like receptor 8

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Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus

Cited by 35 publications

References 40 publications

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

Q493K and Q498H substitutions in Spike promote adaptation of SARS-CoV-2 in mice

Recent Advances in Hepatitis B Treatment

Subtle differences in chemical pattern between human toll‐like receptor 8 agonists and antagonists: Emerging chemical patterns analysis

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