Current Medicinal Chemistry (v.21, #2)
Quantifying Gp96/Grp94 Complexes Preparations for Vaccines: a Key Step Often Inaccurate by A. Seignez, E. Kohli, C. Garrido, R. Seigneuric (153-163).
Glycoprotein 96 (Gp96)-peptide complexes are highly investigated for vaccines preparation, particularly in cancer therapy. Gp96, formerly called tumor rejection antigen (TRA)-1, is able to elicit an immune response that can protect mice against tumors, when the mice share the same haplotype than those bearing the tumors from which Gp96 was purified. Secreted Gp96-peptide complexes act as danger signals thereby stimulating the innate immunity regardless of the chaperoned peptides. In contrast, the tumor rejection antigen role of Gp96-peptide complexes is held by the chaperoned peptides in a dose-dependent manner. The purification step is crucial both for insuring the quality and the quantity of Gp96-peptide complexes. To this aim, different methods have been described but they are often suboptimal for the quantification of these complexes. In this review, we discuss a hot topic: the use of the chaperone Gp96 for vaccination purposes in cancer, and also detail the current methods for quantifying Gp96-peptide preparations.
Isoform Selective Voltage-Gated Sodium Channel Modulators and the Therapy of Pain by Marko Jukic, Danijel Kikelj, Marko Anderluh (164-186).
Voltage-gated sodium channels are large transmembrane protein complexes responsible for the propagation and transmission of electrical impulses through nerve, muscle and endocrine cells and cell systems. Dysregulated expression and/or functional changes of ion channel isoforms are found in many associated pathological conditions. In such cases, modulation of voltage gated sodium channels (NaV channels) is a recognised approach in medicinal chemistry. Multiple small-molecule active compounds are used for a plethora of NaV channel-linked indications, for example epilepsy and CNS disorders, arrhythmia, stroke and pain states such as congenital analgesia/hyperalgesia and neuropathic pain. As existent NaV channel modulators suffer mainly from selectivity issues and thus exert significant side effects, novel and selective NaV channel modulators would be beneficial. Consequently, the increased research on voltage-gated sodium channels has led to a large number of novel compounds that exploit classic binding site selectivity with state-dependence or functional selectivity. Such compounds offer selective targeting and new possibilities for studying the physiology of NaV channels and pathophysiology of the associated ailment conditions. This review consolidates the recent literature on NaV 1.3, 1.7 and 1.8 channel isoform selective and/or state-dependent modulators. In particular, their structure-activity relationship is illustrated, especially in the context of selectivity on a particular isoform, and their applicability in the therapy of neuropathic pain is described.
Recent Development of CB2 Selective and Peripheral CB1/CB2 Cannabinoid Receptor Ligands by Tapio Nevalainen (187-203).
Cannabinoids have potential therapeutic value e.g. in pain relief, cancer therapy, control of nausea and vomiting, and appetite stimulation, but their therapeutic benefits are limited by unwanted central nervous system (CNS) side-effects. Separating the therapeutic effects of cannabinoid agonists from their undesired CNS effects can be achieved by either increasing the selectivity of the ligands for the CB2 receptor or by developing peripherally restricted CB1/CB2 ligands. A vast number of structurally diverse CB2 ligands have been developed during the past 3 years, stemming from the screening hits, which are further optimized towards lead compounds and drug candidates. Some of CB2 ligands may ultimately enter into clinical use as pain relief, anticancer, or antipruritic agents. This review focuses on the recent literature dealing with selective CB2 receptor ligands, with a particular emphasis on the CB2 agonists developed from 2009 onwards.
Curcumin and Curcumin-like Molecules: From Spice to Drugs by A. Marchiani, C. Rozzo, A. Fadda, G. Delogu, P. Ruzza (204-222).
Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine andextensively employed in ayurvedic herbal remedies. A number of studies have shown that curcumin can be a preventionand a chemotherapeutic agent for colon, skin, oral and intestinal cancers. Curcumin is also well known for its antiinflammatoryand antioxidant properties, showing high reactivity towards peroxyl radicals, and thus acting as a free radicalscavenger. Recently, experimental studies have demonstrated that curcumin might be used in the prevention and thecure of Alzheimer's disease. Indeed, curcumin injected peripherally in vivo into aged Tg mice crossed the blood-brain barrierand bound to amyloid plaques, reducing amyloid levels and plaque formation decisively. The present review will resumethe most recent developments in the medicinal chemistry of curcumin and curcumin-like molecules.
Pharmacologic Ovarian Preservation in Young Women Undergoing Chemotherapy by S.T. Chahvar, T. Al-Shawaf, A.L. Tranquilli (223-229).
The prognosis of malignancies in young women undergoing chemotherapy has dramatically improved recently, and more attention is given to the long term quality of life, including fertility and reproductive function preservation. Some chemotherapeutic drugs are known to be associated with gonadal toxicity (cyclophosphamide, L-phenylanine mustard, busulfan and nitrogen mustard) and others have less or un-quantified effects (doxorubicin, bleomycin, vinca alkaloids, as vincristine and vinblastin, cisplatin, nitrosoureas, cytosine arabinoside). Women are in need to identify best options to minimize ovarian damage during chemotherapy through the administration of protective drugs, better choice of therapy and with advocating oncofertility preservation. We reviewed the possible options focusing on the most studied gonadotrophin-releasing hormone agonists (GnRH-a) and the psychologically promising oral contraceptives (OC).Controversy exist on the benefit of gonadotrophin releasing hormone agonist (GnRH-a) or combined oral contraceptive administered at time of cancer therapy in preventing premature ovarian failure in women and the available data from both human and animal studies have been mixed. The best way to preserve fertility and ovarian function in young women undergoing chemotherapy still remains to be determined. In the absence of a best approach, each case should be evaluated individually, considering patient's wishes and expectations, the type of chemotherapy, age, obstetric history, ovarian reserve (combining multiple indicators such as basal hormone profile, anti mullerian hormone -AMH- and antral follicle count), family history of premature ovarian failure. We present a review of the available evidence on the value of administering GnRH-a and OC use to minimize or prevent the effect of chemotherapy agents on reproductive function.
4-Hydroxynonenal in the Pathogenesis and Progression of Human Diseases by Mohammad Shoeb, Naseem H. Ansari, Satish K. Srivastava, Kota V. Ramana (230-237).
Metastable aldehydes produced by lipid peroxidation act as 'toxic second messengers' that extend the injurious potential of free radicals. 4-hydroxy 2-nonenal (HNE), a highly toxic and most abundant stable end product of lipid peroxidation, has been implicated in the tissue damage, dysfunction, injury associated with aging and other pathological states such as cancer, Alzheimer, diabetes, cardiovascular and inflammatory complications. Further, HNE has been considered as a oxidative stress marker and it act as a secondary signaling molecule to regulates a number of cell signaling pathways. Biological activity of HNE depends on its intracellular concentration, which can differentially modulate cell death, growth and differentiation. Therefore, the mechanisms responsible for maintaining the intracellular levels of HNE are most important, not only in the defense against oxidative stress but also in the pathophysiology of a number of disease processes. In this review, we discussed the significance of HNE in mediating various disease processes and how regulation of its metabolism could be therapeutically effective.
HIV-1 Inhibiting Capacity of Novel Forms of Presentation of GB Virus C Peptide Domains is Enhanced by Coordination to Gold Compounds by María J. Gómara, Ramona Galatola, Alejandro Gutiérrez, María C. Gimeno, José M. Gatell, Víctor Sánchez-Merino, Eloísa Yuste, Isabel Haro (238-250).
Following the report of beneficial effects of co-infection by GB virus C (GBV-C) for HIV-infected patients, we have studied synthetic GBV-C peptides and their relationship with HIV type-1. This paper reports the design and synthesis of new forms of presentation of two peptide inhibitors corresponding to the envelope proteins E1 and E2 of GBV-C, together with a study of their anti-HIV-1 activity. Homogeneous and heterogeneous multiple antigenic peptides (MAPs), lipophilic derivatizations, cyclization and peptide-gold conjugations are the chemical design strategies adopted. Our aim is to enhance the anti-viral potency of the GBV-C peptide domains. Of all the GBV-C peptide derivatives studied, peptide-gold complexes derived from the (22-39) sequence of the GBV-C E1 protein were the most active entry inhibitors. These results support the putative modulation of HIV-1 infection by the GBV-C E1 protein and open new perspectives for the development of novel peptide-derived HIV-1 entry inhibitors.
P-glycoprotein and Vacuolar ATPase Synergistically Confer Anthracycline Resistance to Fission Yeast and Human Cells by Zoey Tay, Seok Hwee Koo, Thi Thuy Trang Nguyen, Tsu Soo Tan, Ming Li Chen, Chee Fei Chin, Kim Kiat Lim, Wee Han Ang, Boon Huat Bay, Edmund J.D. Lee, Ee Sin Chen (251-260).
Drug resistance is a major hurdle to the success of chemotherapy. The permeability glycoprotein (P-gp) is animportant factor dictating drug access to the cells, as it controls the efflux of chemotherapeutic agents against the concentrationgradient. Pmd1, a P-gp-like protein, was recently isolated as a doxorubicin resistance gene in fission yeast. Althoughthe null mutant of pmd1 (Δ pmd1) exhibited sensitivity to doxorubicin, it showed an unexpectedly high resistanceto the drug at relatively high concentrations. The data presented here suggest that this is due to the presence of cooperativeprocesses that can complement and counteract drug cytotoxicity in the absence of Pmd1. One such factor, Rav1, is an essentialfactor in controlling the assembly of the pH-regulating transporter vacuolar-ATPase (V-ATPase) in fission yeast.The simultaneous disruption of Pmd1 and Rav1 resulted in a prominent accumulation of doxorubicin in the cytoplasm ofcells, accompanied by a decline in cell viability. With concurrent treatment of pharmacological inhibitors in human cervicalcancer cells, P-gp and V-ATPase were further shown to act synergistically to sensitize cells to doxorubicin also in thehuman cells. Furthermore, a novel Cornichon-like protein SPAC2C4.05 (herein named as Cor1) was demonstrated for thefirst time to be involved in the interaction with P-gp and V-ATPase to counteract doxorubicin-dependent cytotoxicity.Therefore this study identified a molecular cooperation between multiple membrane transporter proteins that conferschemoresistance to cells against the chemical insult of doxorubicin. Interestingly, this network exhibited differential effectsto doxorubicin as compared with its close epimeric analog epirubicin, suggestive of the intricacy of the drug responseregulated by this synergistic interaction. A model is discussed on how the versatility of this network can differentiateclosely related chemical drug structures yet allow for the robustness to counteract a vast range of drugs.