Linear and Rationally Designed Stapled Peptides Abrogate TLR4 Pathway and Relieve Inflammatory Symptoms in Rheumatoid Arthritis Rat Model

Achek, Asma; Shah, Masaud; Seo, Ji Young; Kwon, Hyuk‐Kwon; Gui, Xiangai; Shin, Hyeon Jun; Cho, Eun Young; Lee, Byeong Sung; Kim, Dong Jin; Lee, Sang Ho; Yoo, Tae Hyeon; Kim, Moon Suk; Choi, Sangdun

doi:10.1021/acs.jmedchem.9b00061

Cited by 32 publications

(31 citation statements)

References 69 publications

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“…Modelling procedures for protein-protein docking and interface analyses were performed as previously described (11)(12)(13). Protein surface and patch analyses were performed in MOE suit (2019.0102) as described previously (14).…”

Section: Sars-cov-2 Spike Protein and Antibody Modellingmentioning

confidence: 99%

Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Shah

Ahmad

Choi

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease (COVID-19), is a novel beta coronavirus emerged in China in 2019. Coronavirus uses spike glycoprotein to interact with host angiotensin-converting enzyme 2 (ACE2) and ensure cell recognition. High infectivity of SARS-CoV-2 raises questions on spike-ACE2 binding affinity and its neutralization by anti-SARS-CoV monoclonal antibodies (mAbs). Here, we observed Val-to-Lys417 mutation in the receptor-binding domains (RBD) of SARS-CoV-2, which established a Lys-Asp electrostatic interaction enhancing its ACE2-binding. Pro-to-Ala475 substitution and Gly482 insertion in the AGSTPCNGV-loop of RBD hindered neutralization of SARS-CoV-2 by anti-SARS-CoV mAbs. In addition, we identified unique and structurally conserved conformational-epitopes on RBDs, which can be potential therapeutic targets. Collectively, we provide new insights into the mechanisms underlying the high infectivity of SARS-CoV-2 and development of new effective neutralizing agents.

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Section: Sars-cov-2 Spike Protein and Antibody Modellingmentioning

confidence: 99%

Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Shah

Ahmad

Choi

et al. 2020

Preprint

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“…Structure refinement and optimization of MD-2 binding in silico has proven to be a viable technique in this field, as recently shown by the works of Honegr, Michaeli, and Achek reviewed here ( 30 – 32 , 42 ).…”

Section: Discussionmentioning

confidence: 74%

“…Indeed, cPIP2 showed better inhibitory profile on TLR4 (IC 50 25 μM) and was further tested in vivo in rheumatoid arthritis (RA) mice model. cPIP2 successfully alleviated RA symptoms in mice over a period of 6 weeks, improving histological scores, which suggests the use of cyclic PIP2 as drug lead in RA ( 42 ).…”

Section: Non-glycolipid Tlr4 Modulatorsmentioning

confidence: 89%

“…A phage display (PD) library of 12-mer peptides was constructed by enriching through six rounds of biopanning against hTLR4. One of the five selected peptides, PIP2, a rather hydrophobic 12-mer, inhibited LPS-stimulated TNF-α and IL-6 production in murine and human macrophages with an IC 50 of 40 μM ( 42 ). Besides the relatively weak activity, PIP2 showed some out-of-target inhibitory effects on TLR2.…”

Section: Non-glycolipid Tlr4 Modulatorsmentioning

confidence: 99%

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Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

Romerio

Peri

2020

Front. Immunol.

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Toll-Like Receptor 4 (TLR4) is one of the receptors of innate immunity. It is activated by Pathogen- and Damage-Associated Molecular Patterns (PAMPs and DAMPs) and triggers pro-inflammatory responses that belong to the repertoire of innate immune responses, consequently protecting against infectious challenges and boosting adaptive immunity. Mild TLR4 stimulation by non-toxic molecules resembling its natural agonist (lipid A) provided efficient vaccine adjuvants. The non-toxic TLR4 agonist monophosphoryl lipid A (MPLA) has been approved for clinical use. This suggests the development of other TLR4 agonists as adjuvants or drugs for cancer immunotherapy. TLR4 excessive activation by a Gram-negative bacteria lipopolysaccharide (LPS) leads to sepsis, while TLR4 stimulation by DAMPs is a common mechanism in several inflammatory and autoimmune diseases. TLR4 inhibition by small molecules and antibodies could therefore provide access to innovative therapeutics targeting sepsis as well as acute and chronic inflammations. The potential use of TLR4 antagonists as anti-inflammatory drugs with unique selectivity and a new mechanism of action compared to corticosteroids or other non-steroid anti-inflammatory drugs fueled the search for compounds of natural or synthetic origin able to block or inhibit TLR4 activation and signaling. The wide spectrum of clinical settings to which TLR4 inhibitors can be applied include autoimmune diseases (rheumatoid arthritis, inflammatory bowel diseases), vascular inflammation, neuroinflammations, and neurodegenerative diseases. The last advances (from 2017) in TLR4 activation or inhibition by small molecules (molecular weight <2 kDa) are reviewed here. Studies on pre-clinical validation of new chemical entities (drug hits) on cellular or animal models as well as new clinical studies on previously developed TLR4 modulators are reported. Innovative TLR4 modulators discovered by computer-assisted drug design and an artificial intelligence approach are described. Some “old” TLR4 agonists or antagonists such as MPLA or Eritoran are under study for repositioning in different pharmacological contexts. The mechanism of action of the molecules and the level of TLR4 involvement in their biological activity are critically discussed.

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“…These molecules are upregulated in some patients with RA and are expressed in the synovium 14. Numerous preclinical mechanistic studies have shown the potential role for TLR4 and its ligands in RA 15–24…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study

Monnet¹,

Choy

McInnes

et al. 2019

Ann Rheum Dis

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ObjectivesAnti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes.MethodsPlacebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported.Results90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101.ConclusionsWe demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.

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Linear and Rationally Designed Stapled Peptides Abrogate TLR4 Pathway and Relieve Inflammatory Symptoms in Rheumatoid Arthritis Rat Model

Cited by 32 publications

References 69 publications

Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Sequence variation of SARS-CoV-2 spike protein may facilitate stronger interaction with ACE2 promoting high infectivity

Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview

Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study

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