LIM Kinases (LIMKs) have emerged as critical therapeutic targets in cancer research due to their central role in regulating cytoskeletal dynamics and cell motility via cofilin phosphorylation. Allosteric inhibitors, which bind outside the ATP-binding pocket, offer distinct advantages over ATP-competitive inhibitors, such as increased specificity, reduced off-target effects, and the ability to overcome resistance. This study investigates a series of novel tetrapeptides mimicking the binding mode of TH470, an allosteric LIMK inhibitor, using in silico docking and molecular dynamics simulations to identify potential lead compounds with high specificity, binding affinity, and favorable pharmacokinetic properties. Structural analyses revealed critical interactions between TH470 and LIMKs, particularly with conserved residues such as Thr405 (gatekeeper residue), Ile408 (hinge region), and Asp469 (XDFG motif), which are essential for stabilizing inhibitor binding. Molecular dynamics simulations confirmed the stability of TH470-LIMK1 and TH470-LIMK2 complexes, with lower RMS deviations and robust interaction patterns enhancing binding affinity. From the set of tetrapeptides mimicking TH470 binding mode, only YFYW, WPHW, and YWFP for LIMK1, and PYWG, FYWV, and WFVW for LIMK2 demonstrated high binding affinities, non-toxic profiles, and promising anti-cancer, anti-angiogenic, and anti-inflammatory properties. Among the studied peptides, LIMK1-YFYW and LIMK2-WFVW exhibited the most substantial binding affinities, supported by high hydrogen bond occupancy with key residues such as Ile416 and Thr405. The findings highlight the therapeutic potential of allosteric peptide inhibitors targeting LIMK-mediated pathways in cancer progression. The study underscores the importance of specific interactions with conserved LIMK residues, providing a foundation for further developing selective inhibitors to modulate actin dynamics and combat cancer-related processes.
Trace elements dyshomeostasis affects the physiological processes, metabolism, and immune function and leads to systemic and localised pathologies such as diabetes, cancer, and ocular degenerative diseases. Chelation therapies have been the main mode of treatment but have various side effects, and hence, there is a dire need for new interventions. Chelating and bioactive peptides are emerging as promising therapeutic agents due to their high specificity, potency, low toxicity. This review discusses in detail about these peptides and their applications. This review is based on a thorough literature analysis from PubMed, ScienceDirect, and Google Scholar from 2000 to 2025, with some important older articles included based on their significance. Both experimental and review articles addressing peptides efficacy and potential in systemic and ocular disease were included. Chelating peptides represent a promising and adaptable strategy for correcting metal ion imbalances in the body, with therapeutic potential in areas such as angiogenesis inhibition, modulation of cuproptosis, reduction of oxidative stress, and prevention of fibrillogenesis. A new class of peptides, such as chelating and bioactive peptides, represents a rapidly advancing frontier in precision medicine, offering novel, targeted, and safer alternatives for the treatment of diseases rooted in elemental imbalance and complex molecular dysfunction. This review provides a compendium of current knowledge regarding the general mechanism of these peptides. Bridging the gap between promising preclinical results and clinically viable, patient-friendly therapies, especially achieving effective oral delivery, will be critical for the widespread adoption of peptides in future healthcare. Trace element dyshomeostasis and cellular stress: A New therapeutic approach for therapy.
A 51-year-old Indian man presented with a 2-month history of foot ulcers causing pain on exertion. Examination revealed two shallow, oval ulcers on the right dorsal foot with central eschars (Figure 1a). Inspection of the surrounding skin showed atrophic scarring, suggesting previously healed lesions. The patient had no systemic symptoms and no palpable lymphadenopathy. A diagnosis of vasculitis was considered. The patient presented 3 months later with four new ulcerated and crusted plaques on the right anterior shin (Figure 1b). The previously identified lesions on the right foot had resolved. A skin biopsy of one of the new lesions was performed. Histology revealed widespread epidermal and dermal necrosis with central ulceration. In the dermis, histiocytes, eosinophils, and infiltrates of atypical lymphocytes were found in an angiocentric pattern (Figure 1c). Lymphocytes invading the vessel walls had led to angiodestruction. Immunohistochemical investigations showed that CD2, CD3, CD4, CD5 and CD7 were positive. Additionally, CD30 and CD8 were focally positive (Figure 1d). These findings supported a diagnosis of lymphomatoid papulosis (LyP) type E and treatment was commenced with methotrexate. The ulcers resolved within 6 weeks. Treatment was continued for 12 months and no further lesions were observed. Lymphomatoid papulosis is a rare lymphoproliferative disorder characterized by recurrent papulo-nodular lesions.1 Despite low disease-specific mortality rates, LyP carries a 20% risk of developing secondary lymphoid malignancy.2 Lymphomatoid type E is an uncommon subtype, making up less than 5% of cases.3 It is characterized clinically by lesions that rapidly break down to form large, eschar-like, necrotic ulcers; the other five subtypes differ as smaller superficial ulceration is seen. Ulceration typically resolves spontaneously within 3–6 weeks leaving atrophic varioliform scarring. Histopathological distinction is based on angiocentric CD30+ and CD8+ atypical infiltrates.4 Contradictory to its aggressive presentation, LyP type E has an excellent prognosis; only 5% of patients develop a secondary malignant lymphoma.1 The authors thank Dr. Murugusundaram Sundaram of Chennai Skin Foundation, Chennai and Dr. Sadaf from Apollo Specialties Hospital, Chennai for their work on this case. None declared. Informed consent was provided by the patient for the use of clinical images.
IntroductionInherited retinal diseases (IRDs) are a clinically and genetically heterogenous group where the robust advancement of next-generation sequencing technologies has facilitated genotype-assisted diagnosis. Leber congenital amaurosis (LCA) is a severe form of inherited retinal dystrophy that causes congenital blindness or near-blindness with a global prevalence of 3 per 100,000 live births.It is characterized by a loss of vision at birth or within the first few years of life with overlapping phenotypes to many syndromic and non-syndromic IRDs. With India's rich genetic heterogeneity, WES is a valuable tool for uncovering novel gene mutations linked to LCA. This genetic diversity expands our understanding of the disease's spectrum in the Indian population.MethodsIn our previous study, 92 Indian LCA families were screened through targeted resequencing, and 80% of probands exhibited mutations in known genes. Hence, the remaining 20% probands with additional family members (n = 40) were subjected to whole-exome sequencing. An in-house standard bioinformatics pipeline was used for variant calling and annotation. Homology modeling (Modeller-9.23) and molecular simulation were performed on an identified SLC6A6 gene variant that has not yet been associated with LCA to investigate its potential pathogenicity.ResultsDisease-causing pathogenic variants were identified in 15/20 families (75%) across 11 genes with 33% variants being novel. Among the identified 17 variants in 15 families, 35% were missense, 29% nonsense, 29% frameshift and 6% splice variants. Segregation analysis, control screening and in silico predictions confirmed the variant's pathogenicity. All variants were classified as pathogenic according to ACMG guidelines. Homology modeling and molecular simulation in the membrane system for the p.Pro82Leu mutant in SLC6A6 protein showed significant modification in helical characteristics around the TM2 helix in the mutant, which could potentially hinder the regular function and cause disruption in taurine transport across the membrane leading to the disease.ConclusionTaurine being an essential amino acid for photoreceptor development and maintenance, our study suggests that mutation identified in SLC6A6 gene may cause LCA. This is the first report of SLC6A6 gene association with LCA and also the first case report in the Indian population.
HIV-associated immune activation is characterized by an increase in pro-inflammatory mediators and dysfunctional T-cells with senescent phenotypes. This persistent activation predisposes HIV-infected persons to non-AIDS-defining co-morbid conditions. At the retina, Müller glia undertake innate immune functions. Evidence from our microarray data shows changes in pathways which include cytokines, their receptors, and focal adhesion genes, suggesting inflammatory changes which could affect the blood–retinal barrier. Using a bioinformatics approach, we analyzed our dataset to identify changes in reactive Müller glia. Abnormalities in Müller glia signaling involve phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT). In silico analysis was validated by quantitative RT-PCR. PKB/AKT is increased in reactive Müller glia. Inhibition of PI3K/AKT affected transendothelial resistance in TAT-exposed Müller glia. Identification of a cluster of gene expression suggests underlying changes in the functions of Müller glia in maintaining barrier permeability through the PI3K/AKT signaling network. Activation of retinal Müller cells can therefore lead to pro-inflammatory molecular cascades that promote widespread physiological changes. Alterations in these pathways may affect vascular permeability, retinal and corneal angiogenesis, and disruption of the blood–ocular barrier.
