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Anti-infection | eBiochemicals

eBiochemicals provides information on the Anti-infection: Anti-infectives are drugs that can either kill an infectious agent or inhibit it from spreading. Anti-infectives include antibiotics and antibacterials, antifungals, antivirals and antiprotozoals. Antibiotics specifically treat infections caused by bacteria, most commonly used types of antibiotics are: Aminoglycosides, Penicillins, Fluoroquinolones, Cephalosporins, Macrolides, and Tetracyclines. New other approaches such as photodynamic therapy (PDT) and antibacterial peptides have been considered as alternatives to kill bacteria. The high rates of morbidity and mortality caused by fungal infections are ociated with the current limited antifungal arsenal and the high toxicity of the compounds. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Viral infections occur when viruses enter cells in the body and begin reproducing, often causing illness. Viruses are cl ified as DNA viruses or RNA viruses, RNA viruses include retroviruses, such as HIV, are prone to mutate. The currently available antiviral drugs target 4 main groups of viruses: herpes, hepatitis, HIV and influenza viruses. Drug resistance in the clinical utility of antiviral drugs has raised an urgent need for developing new antiviral drugs. Antiprotozoal drugs are medicines that treat infections caused by protozoa. Of which, malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. At present, antimalarial discovery approaches have been studied, such as the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking.   References: [1] Scorzoni L, et al. Front Microbiol. 2017 Jan 23;8:36. [2] Dehghan Esmatabadi MJ, et al. Cell Mol Biol (Noisy-le-grand). 2017 Feb 28;63(2):40-48. [3] Raymund R, et al. Mayo Clin Proc. 2011 Oct; 86(10):1009-1026. [4] Aguiar AC, et al. Mem Inst Oswaldo Cruz. 2012 Nov;107(7):831-45.

Anti-infection

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Antibody-drug Conjugate/ADC Related | eBiochemicals

eBiochemicals provides information on the Antibody-drug Conjugate/ADC Related: The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel the utic format and has great potential to make a paradigm shift in cancer chemotherapy. The three components of the ADC together give rise to a powerful oncolytic agent capable of delivering normally intolerable cytotoxins directly to cancer cells, which then internalize and release the cell-destroying drugs. At present, two ADCs, Adcetris and Kadcyla, have received regulatory approval with >40 others in clinical development. ADCs are administered intravenously in order to prevent the mAb from being destroyed by gastric acids and proteolytic enzymes. The mAb component of the ADC enables it to circulate in the bloodstream until it finds and binds to tumor-specific cell surface antigens present on target cancer cells. Linker chemistry is an important determinant of the safety, specificity, potency and activity of ADCs. Linkers are designed to be stable in the blood stream (to conform to the increased circulation time of mAbs) and labile at the cancer site to allow rapid release of the cytotoxic drug. First generation ADCs made use of early cytotoxins such as the anthracycline, doxorubicin or the anti-metabolite/antifolate agent, methotrexate. Current cytotoxins have far greater potency and can be divided into three main groups: auristatins, maytansines and calicheamicins. The development of site-specific conjugation methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer the utics.   References: [1] Tsuchikama K, et al. Protein Cell. 2016 Oct 14. DOI:10.1007/s13238-016-0323-0. [2] Peters C, et al. Biosci Rep. 2015 Jun 12;35(4). pii: e00225. doi: 10.1042/BSR20150089.

Antibody-drug Conjugate/ADC Related

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Apoptosis | eBiochemicals

eBiochemicals provides information on the Apoptosis: Cell apoptosis, sometimes called programmed cell death, is a cellular self-destruction method to remove old and damaged cells during development and aging to protect cells from external disturbances and maintain homeostasis. Apoptosis also occurs as a defense mechanism such as in immune reactions or when cells are damaged by disease or noxious agents. Apoptosis is controlled by many genes and involves two fundamental pathways: the extrinsic pathway, which transmits death signals by the death receptor (DR), and the intrinsic or mitochondrial pathway. The extrinsic apoptotic pathway is activated by the binding of the death ligand to DRs, including FasL, TNF-α, and TRAIL, on the plasma membrane. The DR, adaptor protein (FADD), and ociated apoptosis signaling molecule (caspase-8) form the death-inducing signaling complex (DISC), thus leading to the activation of the effector caspase cascade (caspase-3, -6, and -7). The mitochondria-mediated intrinsic apoptosis pathway is regulated by Bcl-2 family proteins, including proapoptotic (Bid, Bax, Bak) and antiapoptotic proteins (Bcl-2, Bcl-xL). Abnormalities in cell apoptosis can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurode-generative diseases. These diseases may benefit from artificially inhibiting or activating apoptosis. A short list of potential methods of anti-apoptotic therapy includes stimulation of the IAP (inhibitors of apoptosis proteins) family of proteins, caspase inhibition, PARP (poly [ADP-ribose] polymerase) inhibition, stimulation of the PKB/Akt (protein kinase B) pathway, and inhibition of Bcl-2 proteins.   References: [1] Susan Elmore. Toxicol Pathol. 2007; 35(4): 495–516. [2] Cao L, et al. J Cell Death. 2016 Dec 29;9:19-29. [3] Dasgupta A, et al. Int J Mol Sci. 2017 Jan; 18(1): 23.

Apoptosis

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Autophagy | eBiochemicals

eBiochemicals provides information on the Autophagy: Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Autophagy plays a wide variety of physiological and pathophysiological roles. Different selective forms of autophagy have been identified and characterized, leading to the specific degradation of organelles or pathogens. These selective pathways include the autophagic degradation of mitochondria (mitophagy), peroxisomes (pexophagy), endoplasmic reticulum (reti phagy or ER-phagy), ribosomes (ribophagy), protein aggregates (aggrephagy), lipid droplets (lipophagy), spermatozoon-inherited organelles following fertilization (allophagy), secretory granules within pancreatic cells (zymophagy), or intracellular pathogens (xenophagy). Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. Autophagy signal transduction are mainly regulated by autophagy-related genes/proteins, Atgs. ATGs have unveiled much of the machinery of autophagosome formation. Furthermore, different non-ATG proteins are involved in the regulation and process of autophagy, e.g., mTOR, AMPK, AKT, AMBRA1, BCL2, DFCP1, or VPS34. Autophagy and its dysregulation have been implicated in different human diseases or processes, such as cancer, neurodegeneration, immunity, or aging. Plenty of drugs and natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways. Small molecules that can regulate autophagy seem to have great potential to modulate the clinical course of neurodegenerative diseases or promote chemothe utic response in tumor models. Besides, several clinical drugs and compounds in diabetes are also found to involve regulation of autophagy.   References: [1] Glick D, et al. J Pathol. 2010 May;221(1):3-12. [2] Mizushima N. Genes Dev. 2007 Nov 15;21(22):2861-73. [3] Wesselborg S, et al. Cell Mol Life Sci. 2015 Dec;72(24):4721-57. [4] Zhang XW, et al. J Nat Prod Res. 2017 Apr;19(4):314-319.

Autophagy

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Cell Cycle/DNA Damage | eBiochemicals

eBiochemicals provides information on the Cell Cycle/DNA Damage: Cell Cycle includes many processes necessary for successful self-replication, and consists of DNA synthesis (S) and mitosis (M) phases separated by gap phases in the order G1–S–G2–M. S phase and M phase are usually separated by gap phases called G1 and G2, when cell-cycle progression can be regulated by various intracellular and extracellular signals. In order to move from one phase of its life cycle to the next, a cell must p through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist. Progression through G1 phase is controlled by pRB proteins, and phosphorylation of pRB proteins by CDKs releases E2F factors, promoting the transition to S phase. The G2/M transition that commits cells to division is a default consequence of initiating the cell cycle at the G1/S transition, many proteins, such Wee1, PLK1 and cdc25, is involved the regulation of this process. The best-understood checkpoints are those activated by DNA damage and problems with DNA replication. DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or byp of DNA damage to ensure the maintenance of genomic stability and cell viability. Genome instability arises if cells initiate mitosis when chromosomes are only partially replicated or are damaged by a double-strand DNA break (DSB). To prevent cells with damaged DNA from entering mitosis, ATR inhibits cyclin B/Cdk1 activation by stimulating the Cdk1 inhibitory kinase Wee1 and inhibiting Cdc25C via Chk1, besides, ATM and ATR also initiate DNA repair by phosphorylating several other substrates. In cancer cells, the cell cycle regulators as well as other elements of the DDR pathway have been found to protect tumor cells from different stresses and to promote tumor progression. Thus, cell cycle proteins that directly regulate cell cycle progression (such as CDKs), as well as checkpoint kinases, Aurora kinases and PLKs, are promising targets in cancer therapy.   References: [1] Rhind N, et al. Cold Spring Harb Perspect Biol. 2012 Oct; 4(10): a005942. [2] Duronio RJ, et al. Cold Spring Harb Perspect Biol. 2013 Mar; 5(3): a008904. [3] Liu W, et al. Mol Cancer. 2017 Mar 14;16(1):60. [4] Ghelli Luserna di Rora' A, et al. J Hematol Oncol. 2017 Mar 29;10(1):77.

Cell Cycle/DNA Damage

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