Oxidation State Dependent Conformational Changes of HMGB1 Regulate the Formation of the CXCL12/HMGB1 Heterocomplex

Fassi, Enrico M. A.; Sgrignani, Jacopo; D’Agostino, Gianluca; Cecchinato, Valentina; Garofalo, Maura; Grazioso, Giovanni; Uguccioni, Mariagrazia; Cavalli, Andrea

doi:10.1016/j.csbj.2019.06.020

Cited by 19 publications

(23 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CXCL12/CXCR4 antagonists have shown encouraging results in reducing the enhanced survival and proliferation of leukemia cells and sensitizing leukemia cells to chemotherapy [ 60 , 61 ]. During inflammation or tissue damage, extracellular fr-HMGB1 exerts chemotactic activity and enhances leukocyte recruitment by forming a heterocomplex with CXCL12 and binding to CXCR4 [ 31 , 62 , 63 ]. It has been found that the IKKα/noncanonical NF-κB pathway is required for sustained CXCL12/SDF-1 production to induce migration toward HMGB1, indicating that the heterocomplex of HMGB1 and CXCL12/SDF-1 may induce cell migration through the NF-κB pathway [ 64 ].…”

Section: Overview Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

View full text Add to dashboard Cite

High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.

show abstract

Section: Overview Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…2a Breaks the HMGB1•CXCL12 Heterocomplex NMR titrations and HADDOCK calculations indicate that 2a targets in part the region that has been shown to be involved in the interaction with CXCL12 (Schiraldi et al, 2012;De Leo et al, 2019;Fassi et al, 2019). We therefore asked whether 2a was able to interfere with the HMGB1•CXCL12 heterocomplex ( Figure 7A).…”

Section: D Model Of the Interactions Of 2a With Hmgb1 Boxesmentioning

confidence: 99%

“…Interference with this heterophilic interaction is attractive but challenging for several reasons: (i) the three-dimensional structure of the complex is still unknown, and (ii) the interaction surface is expected to be large and dynamic, thus difficult to be targeted by small molecules (Schiraldi et al, 2012;De Leo et al, 2019;Fassi et al, 2019). Previous work has shown that it is possible to interfere with the pro-inflammatory properties of HMGB1 using small molecules including glycyrrhizin (Mollica et al, 2007), salicylic acid (SA), and its derivative amorfrutin (Choi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 5,5′-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation

et al. 2020

View full text Add to dashboard Cite

HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates in the recruitment of inflammatory cells, forming a heterocomplex with the chemokine CXCL12 (HMGB1·CXCL12), thereby activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation-related diseases. To identify new HMGB1·CXCL12 inhibitors we have performed a study on the ligandability of the single HMG boxes of HMGB1 followed by a virtual screening campaign on both HMG boxes using Zbc Drugs and three different docking programs (Glide, AutoDock Vina, and AutoDock 4.2.6). The best poses in terms of scoring functions, visual inspection, and predicted ADME properties were further filtered according to a pharmacophore model based on known HMGB1 binders and clustered according to their structures. Eight compounds representative of the clusters were tested for HMGB1 binding by NMR. We identified 5,5′-methylenedi-2,3-cresotic acid (2a) as a binder of both HMGB1 and CXCL12; 2a also targets the HMGB1·CXCL12 heterocomplex. In cell migration assays 2a inhibited the chemotactic activity of HMGB1·CXCL12 with IC50 in the subnanomolar range, the best documented up to now. These results pave the way for future structure activity relationship studies to optimize the pharmacological targeting of HMGB1·CXCL12 for anti-inflammatory purposes.

show abstract

“…This analysis disclosed that the HBP08 binding site on BoxA is formed by some residues Ala17, Val20, Arg24 and Glu25, important also for the CXCL12 binding. 13 Therefore, the peptide binding might antagonize by competition the formation of the CXCL12/HMGB1 heterocomplex.…”

Section: Characterization Of the Hmgb1-hbp08 Interactionmentioning

confidence: 99%

“…12 Reduced HMGB1, once released in the extracellular space, can form a heterocomplex with CXCL12 and synergistically promote, via CXCR4, the recruitment of leukocytes to inflammatory sites. 7,8,13 Moreover reduced HMGB1 can bind to the receptor for advanced glycation endproducts (RAGE) to induce CXCL12 secretion and authophagy. 14…”

Section: Introductionmentioning

confidence: 99%

Systematic development of peptide inhibitors targeting the CXCL12/HMGB1 interaction

Sgrignani¹,

Cecchinato²,

Fassi

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

During inflammatory reactions, the production and release of chemotactic factors guide the recruitment of selective leukocyte subpopulations. HMGB1 and the chemokine CXCL12, both released in the microenvironment, form a heterocomplex, which exclusively acts on the chemokine receptor CXCR4, enhancing cell migration and, in some pathological conditions such as Rheumatoid Arthritis, exacerbating the immune response. An excessive cell influx at the inflammatory site can be diminished by disrupting the heterocomplex.Here, we report the computationally driven identification of a novel peptide (HBP08), which binds HMGB1 with the highest affinity reported so far (K d of 0.8 ± 0.1 μM), able to selectively inhibit the activity of the CXCL12/HMGB1 heterocomplex.The identification of this peptide represents an important step towards the development of innovative pharmacological tools for the treatment of severe chronic inflammatory conditions characterized by an uncontrolled immune response. KeywordsPeptide inhibitors, computational drug design, cell migration, inflammation, HMGB1, CXCL12, CXCL12/HMGB1 heterocomplex

show abstract

Oxidation State Dependent Conformational Changes of HMGB1 Regulate the Formation of the CXCL12/HMGB1 Heterocomplex

Cited by 19 publications

References 56 publications

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

Discovery of 5,5′-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation

Systematic development of peptide inhibitors targeting the CXCL12/HMGB1 interaction

Contact Info

Product

Resources

About