Snakes are fascinating creatures and have been residents of this planet well before ancient humans dwelled the earth. Venomous snakes have been a figure of fear, and cause notable mortality ...throughout the world. The venom constitutes families of proteins and peptides with various isoforms that make it a cocktail of diverse molecules. These biomolecules are responsible for the disturbance in fundamental physiological systems of the envenomed victim, leading to morbidity which can lead to death if left untreated. Researchers have turned these life-threatening toxins into life-saving therapeutics via technological advancements. Since the development of captopril, the first drug that was derived from bradykininpotentiating peptide of Bothrops jararaca, to the disintegrins that have potent activity against certain types of cancers, snake venom components have shown great potential for the development of lead compounds for new drugs. There is a continuous development of new drugs from snake venom for coagulopathy and hemostasis to anti-cancer agents. In this review, we have focused on different snake venom proteins / peptides derived drugs that are in clinical use or in developmental stages till to date. Also, some commonly used snake venom derived diagnostic tools along with the recent updates in this exciting field are discussed.
Flavonoids are new promising potential natural compounds for treating Alzheimer's disease (AD). Actually most promising drugs for symptomatic treatment of AD are acetylcholinesterase inhibitors ...(AChEI). Flavonoids with AChE inhibitory activity and due to their well known antioxidant activity could be new multipotent drugs for AD treatment. This work focuses on natural and synthetic flavonoids inhibitors of the enzyme acetylcholinesterase (AChE). Over, all this review refers to 128 flavonoids, which are classified in chemical structure, and summarizes 64 references.
Post translational modification of histones and non-histone proteins by acetylation play a key role in tumourigenesis. Histone deacetylases (HDACs) are enzymes involved in remodelling of chromatin by ...deacetylating the lysine residues and play a pivotal role in epigenetic regulation of gene expression. An aberrant activity of HDACs has been documented in several types of cancers and HDACs have emerged as an attractive therapeutic target. HDAC inhibitors (HDACi) are a structurally diverse group of anti-cancer agents which have a potential role in regulation of gene expression and induction of cell death, cell cycle arrest, and differentiation by altering the acetylation status of histone and non-histone proteins. HDACi have pleiotropic effects on malignant cells and have demonstrated potent anti-cancer activity in pre-clinical studies. A number of clinical trials of HDACi as a monotherapy and/or in combination with conventional and novel chemotherapeutic drugs in solid and haematologic tumours have been published with variable efficacy.
Within the flavonoid class of natural products the prenylated sub-class is quite rich in structural variety and pharmacological activity. In the last twenty years a huge number of new structures has ...been reported, mostly from Leguminosae and Moraceae, with few coming from other genera. The presence, in different forms, of the isoprenoid chain can lead to impressive changes in biological activity, mostly attributed to an increased affinity for biological membranes and to an improved interaction with proteins. Molecules, such as xanthohumol and sophoraflavanone G, while being very structurally simple, show numerous pharmacological applications and are ideal candidates for SAR aimed to the discovery of new drugs. Only recently the biogenesis of these compounds has been more extensively studied and much attention has been focused on the enzymes involved in the modification and transfer of the prenyl unit.
Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, ...glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.
There is a need for novel drugs for the treatment of infectious diseases, autoimmunity and cancer. Cyclic peptides constitute a class of compounds that have made crucial contributions to the ...treatment of certain diseases. Penicillin, Vancomycin, Cyclosporin, the Echinocandins and Bleomycin are well-known cyclic peptides. Cyclic peptides, compared to linear peptides, have been considered to have greater potential as therapeutic agents due to their increased chemical and enzymatic stability, receptor selectively, and improved pharmacodynamic properties. They have been used as synthetic immunogens, transmembrane ion channels, antigens for Herpes Simplex Virus, potential immunotherapeutic vaccines for diabetes and Experimental Autoimmune Encephalomyelitis - an animal model of Multiple Sclerosis, as inhibitors against α-amylase and as protein stabilizers. Herein, we review important cyclic peptides as therapeutic agents in disease.
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic ...process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years.With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available threedimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.
West Nile Virus (WNV) has spread rapidly during the last decade across five continents causing disease and fatalities in humans and mammals. It highlights the serious threat to both our health and ...the economy posed by viruses crossing species, in this case from migratory birds via mosquitoes to mammals. There is no vaccine or antiviral drug for treating WNV infection. One attractive target for antiviral development is a viral trypsin-like serine protease, encoded by the N-terminal 184 amino acids of NS3, which is only active when tethered to its cofactor, NS2B. This protease, NS2B/NS3pro, cleaves the viral polyprotein to release structural and non-structural viral proteins that are essential in viral replication and assembly of new virus particles. Disruption of this protease activity is lethal for virus replication. The NS3 protein also has other enzymes within its sequence (helicase, nucleoside triphosphatase, RNA triphosphatase), all of which are tightly regulated through localisation within membranous compartments in the infected cell. This review describes the various roles of NS3, focussing on NS2B-NS3 protease and its function and regulation in WNV replication and infection. Current advances towards development of antiviral inhibitors of NS2B/NS3pro are examined along with obstacles to their development as an antiviral therapy.
Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics. Many therapeutically useful drugs are metabolized by these proteins which impacts upon the efficiency ...of drug treatment. In some instances, CEs convert inactive prodrugs to active metabolites, a process that is essential for biological activity. Such compounds include the anticancer agents CPT-11 (3) and capecitabine (4), the antibiotics Ceftin (9) and Vantin, as well as the illicit street drug heroin (6). However, more commonly, CEs hydrolyze many esterified drugs to inactive products that are then excreted. Agents such as flestolol (11), meperidine (5), lidocaine (8) and cocaine (7), are all hydrolyzed and inactivated by these enzymes. Therefore the efficacy of esterified drugs will be dependent upon the distribution and catalytic activity of different CEs. In this review, we examine the structural aspects of CEs and their roles in drug detoxification and propose that modulation of CE activity may allow for improvements in, and potentiation of, drug efficacy.
Although chemotherapy is considered the mainstay of cancer therapy, unfortunate side effects of chemotherapy create a continuous demand for developing other novel and specific targets for cancer ...therapy. Re-expression of epigenetically silenced tumor suppressor genes is a rational strategy for the treatment of human neoplasms. Epigenetic modifiers like DNA methyltransferase (DNMT) inhibitors and histone deacteylase (HDAC) inhibitors induce the re-expression of epigenetically silenced genes in vitro and in vivo. Moreover, they demonstrate safety and efficacy against neoplastic diseases in clinical trials. DNMT inhibitors like 5-azacytidine and 5-aza-2'-deoxycytidine are currently FDA approved for the treatment of myelodysplastic syndrome. Nonetheless, the mechanism of action behind their clinical efficacy remains unclear. Ongoing clinical trials are attempting to identify tumor suppressor genes that upon re-expression can induce remission and cure in patients. On the other hand, the pleiotropic biological effects of DNMT inhibitors and recent reports demonstrating lack of association between clinical response and methylation reversal of candidate tumor suppressor genes, suggest a complex mechanism behind their clinical efficacy that may involve a cytotoxic effect.
