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Computational characterization and integrative analysis of proteins involved in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Pranitha Jenardhanan, Manivel Panneerselvam, Premendu P. Mathur
In addition to the studies aimed at improving efficacy of adjudin, other studies were also conducted to identify new promising leads that can be used as male contraceptives. In a study conducted by Jenardhanan et al., the authors analyzed the structure of MARK4,114 which is shown to be important in conferring polarity to maturing spermatids that are attached with apical ES and targeted inhibition of MARK4 is shown to impair spermatogenesis, resulting in premature release of immature spermatid into the lumen. In this study, the authors predicted the three-dimensional conformation for the kinase-UBA construct of MARK4 and identified MARK4-specific inhibitors.114 MARK4 belongs to the serine/threonine kinases and is the mammalian homolog of partition-defective 1 protein. MARK4 has four important regions: N-terminal kinase domain, autoregulatory UBA domain, disordered spacer region, and a terminal kinase-associated domain. As a means of identifying novel inhibitors for MARK4, the authors have predicted the structure for the kinase–UBA construct in an inactive catalytic conformation and revealed that MARK4 has unique structural features such as DFG-in-αC-helix-out inactive conformation that differentiates it from other ser/thr kinases. The presence of a unique DFG-in-αC-helix-out mode necessitates the design of MARK-specific inhibitors. In doing this, the authors utilized the pharmocophoric feature of 9-oxo derivatives that are shown to be MARK-specific and used them to screen a library of kinase inhibitors. The results identified 10 potent leads that on molecular dynamics simulation study maintained their binding association and showed steady pulling of N- and C-terminal lobes of kinase domain, thereby arresting the catalytic conformation from phosphorylating its substrates. The identified leads function as potent ATP competitors such that with unique DFG-in conformation they can be used to inhibit both active and inactive states of MARK4, thus favoring their selection for the design of next generation nonhormonal contraceptives. There are few studies that illustrate how structural bioinformatics can be used to understand the underlying structural mechanism behind the biological function of selected biomarkers.
Recent advances in anti-multidrug resistance for nano-drug delivery system
Published in Drug Delivery, 2022
Changduo Wang, Fashun Li, Tianao Zhang, Min Yu, Yong Sun
Ion homeostasis in cells is closely related with intracellular energy metabolism and further affects the tumor drug efflux pump activity. Adjudin, a chloride ion channel blocker, could affect mitochondria function that is initially used for researching sperm activity and contraception. Furthermore, recent studies showed that it could restrain tumor growth and be applied in reversing MDR (Wang et al., 2019c). Tumor cells are more sensitive to Ca2+ compared with normal cells because it lacks a sufficient Ca2+ metabolism pathway; meanwhile, intracellular Ca2+ overload can disturb the tricarboxylic acid cycle, reduce the oxygen consumption, and suppress the overexpression of P-gp caused by downregulating HIF-1α. Liu et al. prepared a tumor targeting “calcium ion nanogenerator” to deliver Ca2+ and DOX into tumor cells and reverse MDR through an intracellular Ca2+ bursting strategy (Liu et al., 2020a). Due to excessive Ca2+ providing a survival pathway for cancer cells, higher cellular Ca2+ is generally recognized as an important resistance characteristic. The phytic acid (PA)-modified CeO2 nanoinhibitors were designed to reverse MDR through an efficient inhibiting Ca2+ (Tian et al., 2022) (Table 4).
Adjudin-loaded redox-sensitive paclitaxel-prodrug micelles for overcoming multidrug resistance with efficient targeted Colon cancer therapy
Published in Drug Delivery, 2020
Deli Chen, Sitang Ge, Lugen Zuo, Shuanhu Wang, Mulin Liu, Shiqing Li
Adjudin (ADD), an analogue of lonidamine, is a powerful inhibitor of mitochondrial function (Xie et al., 2013). ADD is able to induce mitochondrial dysfunction, resulting in the severe disruption of energy supply and inhibition of the ATP-dependent efflux transporter, P-gp, ultimately reversing MDR (Li et al., 2015; Qi et al., 2018; Wang et al., 2019). Several previous studies have demonstrated that the co-delivery of ADD and doxorubicin (DOX) effectively reverses MDR in breast cancer (Li et al., 2015; Qi et al., 2018; Wang et al., 2019). It has also been reported that the co-delivery of two drugs, at an optimized ratio, and with rapidly and completely intracellular drug release, can achieve best therapeutic effects (Xiaopin et al., 2013; Yang et al., 2019). A previous report solved the problem of co-delivering ADD and DOX at an optimal ratio by utilizing a pH-sensitive prodrug nanosystem (Wang et al., 2019). However, the total amount of DOX that was released within 72 h at pH 5.0 was lower than 30%. Thus, by developing an appropriate nanocarrier for the co-delivery of chemotherapeutic drugs and ADD, with an optimized ratio and maximal levels of intracellular drug release, may significantly improve the combination effect.
An overview of properties of Amphora (Acidform) contraceptive vaginal gel
Published in Expert Opinion on Drug Safety, 2018
Other mechanisms of action have been tested for vaginal contraception. There has been particular interest in identifying target ion channels in sperm that could be manipulated to kill or inactivate the sperm after ejaculation [34]. Investigation of several other cationic surfactants such as benzalkonium bromide, pyridinium bromide, and dodecyl trimethylammonium bromide, has suggested they may also act by increasing calcium signaling and promoting higher calcium flux [35]. Adjudin is another agent that has been found to inhibit sperm capacitation in part by impeding chloride ion transport in the sperm [36]. Other Catsper calcium channel or soluble sodium–hydrogen exchanges, and soluble adenylyl cyclase are all excellent targets which excellent targets which would have great potential as vaginal spermicides, but inhibitors for them have not yet been identified [37]. Natural products with unspecified mechanisms of action have been tested in earlier stage studies. Oleanolic acid 3-beta-D-glucuronide at 50 mcg 1 mL doses are 100% spermicidal [38] and extracts from Achyranthes aspera and Stephania hernandifolia immobilize sperm in 20 s [39].