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Miscellaneous Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
Tacrolimus is a macrolide immunosuppressant, used to prevent solid organ rejection after transplantation (Scott et al., 2003). Tacrolimus decreases T-cell production through binding to an immunophilin, FK506 binding protein (FKBP), inhibiting calcineurin phosphatase. This inhibits downstream calcium-dependent events, such as interleukin-2 gene transcription, nitric oxide synthase activation, cell degranulation, and apoptosis, inhibiting T-cell production. Several small case series or case reports of the use of tacrolimus during pregnancies of transplant patients are published (Jain et al., 1993; Laifer et al., 1994; Yoshimura et al., 1996). No birth defects or adverse pregnancy outcomes were reported, except for slightly reduced birth weight and transient immunocompromise.
Tacrolimus
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Tacrolimus is a macrolide immunosuppressive drug obtained from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis. Tacrolimus binds to the FKBP-12 protein and forms a complex with calcium-dependent proteins, thereby inhibiting calcineurin phosphatase activity and resulting in decreased cytokine production. This agent exhibits potent immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation. Tacrolimus is used orally after allogenic organ transplantation for immunosuppression to reduce the risk of organ rejection. It is also widely utilized topically for the treatment of atopic dermatitis, severe refractory uveitis after bone marrow transplantation, and vitiligo (1).
Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
Rapamycin is another macrolide immunosuppressant structurally similar to but functionally different from tacrolimus. Rather than inhibiting cytokine synthesis, rapamycin blocks lymphocyte proliferation. Rapamycin binds to the family of FK binding proteins (FKBPs), and the rapamycin-FKBP complex inhibits the activation of the p70S6k kinase [171,172]. Subsequently, there is decreased kinase activity of other cyclin proteins, and cell entry from the G1 to the S phase of the cell cycle is blocked [173,174]. The end result is that the cellular proliferative responses induced by cytokines or growth factors (including IL-1, IL-2, IL-3, IL-6, and basic fibro-blast growth factor [bFGF]) are dramatically reduced [174]. In addition to effects on T lymphocytes, rapamycin can also inhibit B lymphocyte activation and differentiation [175].
The prediction of protein–ligand unbinding for modern drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Qianqian Zhang, Nannan Zhao, Xiaoxiao Meng, Fansen Yu, Xiaojun Yao, Huanxiang Liu
Wexplore is an effective method for the simulation of protein–ligand dissociation that was developed by Dickson and Brooks [23]. It is an extension of the weighted ensemble (WE) algorithm. By defining regions hierarchically, Wexplore solves the limitation encountered by the application of the WE algorithm in high-dimensional spaces that require a large number of regions. Wexplore can predict the dissociation pathway and RT of a ligand without the introduction of a bias potential. This method was first applied in a study on the unbinding of the FK506 binding protein (FKBP) and its three ligands [100]. The binding affinities of the ligands were ranked through the MFPT calculation of unbinding and were found to be consistent with the experimental results. Wexplore has also been applied to predict the RTs of trypsin–benzamidine [101] and soluble epoxide hydrolase systems [102]. In addition, given that the Wexplore sampling method obtains unbiased trajectories, it can be combined with the MSM method [102,103] to construct conformation space networks that can further be utilized to investigate the complete free energy landscape and identify major transition intermediates.
The role of mTOR in age-related diseases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca
The immunosuppressive activity of rapamycin was first evidenced by its ability to decrease humoral IgE production in rats and its preventive effects in two animal models of human autoimmune diseases5. Only the discovery of the immunosuppressive drug FK506 (tacrolimus) by the Fujisawa Pharmaceutical Laboratories drew more attention than rapamycin as an immunosuppressant. Both FK506 and rapamycin contain macrolactam rings with hemiketal-masked diketopipecolic acid amidic components that bind to the identical family of intracellular receptors. Despite these similarities, the mechanism of action of rapamycin is distinct from that of FK506. While FK506 binds to the immunophilin (peptidyl-prolyl cis/trans isomerase FKBP12, E.C. 5.2.1.8) receptor resulting in an immunophilin–drug complex with inhibitory effects against the activity of calcineurin (T cell antigen receptor activating enzyme), the rapamycin–immunophilin complex interferes with T cell growth factors. Nevertheless, both rapamycin and tacrolimus have significant clinical implications, since both are approved for use in prophylaxis for renal rejection6–9.
A Novel AIPL1 Nonsense Mutation: Case Report of Three Siblings Diagnosed with Leber Congenital Amaurosis
Published in Fetal and Pediatric Pathology, 2020
The centrosomal protein, 290-kd (CEP290) is the most commonly affected gene, while the most severe phenotypes occur as a result of mutations in the genes guanylate cyclase 2D (GUCY2D) and aryl hydrocarbon receptor interacting protein-like 1 (AIPL1). FKBP-domain proteins (FKBPs) are main modulators of cellular pathway and gene transcription. The AIPL1 is a prominent member of the FKBP superfamily in terms of its biological properties, and it plays a significant vital role as a chaperone of phosphodiesterase 6 (PDE6), an equalizer enzyme of the optical transduction cascade. This codifying protein includes three tetratricopeptide motifs with chaperone or nuclear transport activity. The lack of AIPL1 protein results in degeneration of rod and cone cells and a loss of light-dependent electrical reply. Variants in AIPL1 (LCA4, MIM #604393) are linked with a severe congenital LCA phenotype, with rapidly progressive visual impairment, accounting for less than 10% of LCA. To date, more than 75 AIPL1 mutations have been identified according to the HGMD Professional 2018.3 (http://www.hgmd.org). The p.W278X mutation is the most common mutation in different populations [2–4].