Allosteric inhibition abrogates dysregulated LFA-1 activation: Structural insight into mechanisms of diminished immunologic disease

Abdullahi, Maryam; Olotu, Fisayo A.; Soliman, Mahmoud E. S.

doi:10.1016/j.compbiolchem.2018.02.002

Cited by 27 publications

(18 citation statements)

References 43 publications

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“…Structural studies and characterization of LFA‐1 have previously revealed the involvement of the α‐7 helix in regulating the open‐closed conformation of LFA‐1 . The open conformation represents the high‐affinity state that is suitable for binding small molecule compounds and other biological molecules such as ICAM and LtxA while the low‐affinity state represents the inactive LFA‐1 state .…”

Section: Resultsmentioning

confidence: 99%

“…The open conformation represents the high‐affinity state that is suitable for binding small molecule compounds and other biological molecules such as ICAM and LtxA while the low‐affinity state represents the inactive LFA‐1 state . Previously, pharmacological agents such as lifitegrast, a well‐known LFA‐1 antagonist, have been shown to elicit its therapeutic function by restoring an active LFA‐1 to its low‐affinity state preventive of ICAM binding . This accounts for its efficacy in the treatment of dry eye disease .…”

Section: Resultsmentioning

confidence: 99%

“…Structural studies and characterization of LFA-1 have previously revealed the involvement of the α-7 helix in regulating the open-closed conformation of LFA-1. 27,31 The open conformation represents the high-affinity state that is suitable for binding small molecule compounds and other biological molecules such as ICAM and LtxA while the low-affinity state represents the inactive LFA-1 state. 29 Previously, pharmacological agents such as lifitegrast, a well-known LFA-1 antagonist, have been shown to elicit its therapeutic function by restoring an active LFA-1 to its low-affinity state preventive of ICAM binding.…”

Section: Ltxa Antagonists Elicit An Upward Pull Of the α-7 Helixmentioning

confidence: 99%

“…13,28 Likewise, LFA-1 can exist in the active (open/exposed) or inactive (closed) states, which is characterized by different affinity states and conformational attributes ( Figure 2). 27,31 The active conformation of LFA-1 is important for its interaction with intrinsic or extrinsic ligands relative to signaling functions. 24,29,31,32 Likewise, LtxA specifically target the active/exposed conformation of LFA-1.…”

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confidence: 99%

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Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Abdullahi

Olotu

Soliman

2018

J of Cellular Biochemistry

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Aggregatibacter actinomycetemcomitans is a Gram-negative bacteria that has gained wide recognition for its causative role in the development of various immune diseases, which includes localized aggressive periodontitis. Its ability to evade host defense mechanisms is mediated by the secretion of leukotoxin (LtxA), which induces death of white blood cells (leukocytes) by specific binding to their surface-expressed leukocyte function-associated receptor (LFA-1) in its active state. Therapeutic compounds that interfere with this pathogenic process and abrogate A. actinomycetemcomitans virulence have been reported in literature. These include doxycycline, and more recently phytochemical compounds such as hamamelitanin, resveratrol, naringin, and quercetin. However, the question remains how do they work? Therefore, with the aid of computational tools, we explore the molecular mechanisms by which they possibly elicit their therapeutic functions. Molecular mechanics Poisson/Boltzmann surface area analyses revealed that these compounds bind favorably to active LFA-1 with high affinity and considerable stability, indicative of their ability to occupy the LtxA binding site (LBS) and prevent LtxA binding. The conformational transition of open LFA-1 to its closed state further describe the mechanistic activity of these compounds. In addition to notable reductions in structural mobility and flexibility, the burial of surface-exposed interactive side chains at the LBS was observed, an occurrence that could alter the complementary binding of LtxA. It is also important to mention that these occurrences were induced more prominently by the phytochemicals. We believe that these findings will enhance the scope of drug design and discovery for potent LtxA antagonists with improved activities and therapeutic efficacies in the treatment of virulent A. actinomycetemcomitans diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Ltxa Antagonists Elicit An Upward Pull Of the α-7 Helixmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Abdullahi

Olotu

Soliman

2018

J of Cellular Biochemistry

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“…LFA-I is the most abundant and widespread integrin expressed in all human T cells [ 109 , 121 ], playing a pivotal role in T lymphocytes function and mediating cell adhesion, the migration of T cells from the lymph nodes to the inflammatory sites, and antigen presentation [ 121 , 122 ]. In addition to interacting with members of the immunoglobulin superfamily present on the endothelium known as an intercellular adhesion molecule (ICAM)-1, ICAM-2, vascular cell adhesion molecule (VCAM)-1, and mucosal addressin cell adhesion molecule (MAdCAM)-1 [ 121 ], LFA-I also interacts with ICAM-1 present on the antigen-presenting cell surface [ 123 ].…”

Section: Co-stimulatory Molecules and Their Role In Chagas Diseasementioning

confidence: 99%

The Role of Co-Stimulatory Molecules in Chagas Disease

Pinto

Medeiros

Fontes-Cal

et al. 2018

Cells

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Chagas disease, caused by Trypanosoma cruzi, is a potentially life-threatening tropical disease endemic to Latin American countries that affects approximately 8 million people. In the chronic phase of the disease, individuals are classified as belonging to the indeterminate clinical form or to the cardiac and/or digestive forms when clinical symptoms are apparent. The relationship between monocytes and lymphocytes may be an important point to help clarify the complexity that surrounds the clinical symptoms of the chronic phase of Chagas disease. The co-stimulatory signals are essential to determining the magnitude of T cell response to the antigen. The signals are known to determine the regulation of subsequent adaptive immune response. However, little is known about the expression and function of these molecules in Chagas disease. Therefore, this review aims to discuss the possible role of main pathways of co-stimulatory molecule-receptor interactions in this pathology that could be crucial to understand the disease dynamics.

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Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

et al. 2022

Med Chem Res

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The interaction between Lymphocyte function-associated antigen 1 (LFA-1) and intercellular-adhesion molecule-1 (ICAM-1) plays important roles in the cell-mediated immune response and inflammation associated with dry eye disease. LFA-1/ICAM-1 antagonists can be used for the treatment of dry eye disease, such as Lifitegrast which has been approved by the FDA in 2016 as a new drug for the treatment of dry eye disease. In this study, we designed and synthesized some new structure compounds that are analogues to Lifitegrast, and their biological activities were evaluated by in vitro cell-based assay and also by in vivo mouse dry eye model. Our results demonstrated that one of these analogues of Lifitegrast (compound 1b) showed good LFA-1/ICAM-1 antagonist activity in in vitro assay; meanwhile, it also significantly reduced ocular surface epithelial cells damage, increased goblet cell density in dry eye mouse and highly improved the symptoms of dry eye mouse.

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Allosteric inhibition abrogates dysregulated LFA-1 activation: Structural insight into mechanisms of diminished immunologic disease

Cited by 27 publications

References 43 publications

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

Solving the riddle: Unraveling the mechanisms of blocking the binding of leukotoxin by therapeutic antagonists in periodontal diseases

The Role of Co-Stimulatory Molecules in Chagas Disease

Design, synthesis, and LFA-1/ICAM-1 antagonist activity evaluation of Lifitegrast analogues

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