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Therapeutic proteins are an important class of drugs, representing about one third of new drug approvals. Various engineering techniques can be used to improve the pharmacokinetic properties of therapeutic proteins, such as fusion proteins, PEGylation, codon optimization, and sequence alterations. Computational drug design techniques are also widely used in China for drug discovery, including molecular docking, virtual screening, target identification, and predicting drug properties. The Hippo signaling pathway regulates organ size and tumorigenesis, and its dysregulation can promote cancer; targeting this pathway may yield new anticancer therapies. Influenza's M2 proton channel is a drug target; while current channel blockers like amantadine face resistance, new inhibitors are being
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- 2. Contents
- 3. Building better drugs: developing and regulating engineered therapeutic proteins Therapeutic proteins Although a reliable count of functionally distinct proteins in humans is lacking, estimates suggest that the number runs to at least several tens of thousands Abnormality in one or more of these proteins leads to disease condition Therapeutic proteins represented 17% of new drugs approved by the USA Food and Drug Administration (FDA) in 2005 but increased to 32% by 2011 Factors VIII and IX as replacement therapy for hemophilia has significantly extended the life expectancy of patients Withdrawals Due to safety issues Vatreptacog alpha, BAY86-6150 bioengineered recombinant factor VIIa Hypersensitivity reactions Peginesatide, a novel functional analog of erythropoietin
- 4. Engineered proteins: therapeutics by design Need- very short serum half-life and poor bioavailability heterologous expression systems such as E. coli or yeast lack post- translational modifications Technologies: Fusion proteins- unstructured recombinant polypeptides called XTEN have been successfully used to generate fusion proteins with improved pharmacokinetic properties Also PEGylated proteins Alteration of sequence Deletions, insertions, and point mutations in a wild type sequence are performed eg. deletion of the B-domain of Factor VIII results in higher secretion of the protein into the media as compared with the full-length form of Factor VIII Codon optimization Codon optimization is a technique to maximize the protein expression Reports increase up to 30-fold Codon optimization softwares-GENEMAKER, General Codon Usage Analysis (GCUA) -a program Gene composer, Gene designer, JCat , Optimizer etc
- 5. Concluding remarks There has been unprecedented progress, during the past decade, in the development of platform technologies that further being improved The rapid progress of many different scientific disciplines holds promise for more predictable criteria for the licensure of these products And less burdensome regulatory requirements
- 6. Pharmacology in China: Overview 1. Formation(1923–1949) Part of Chinese civilization for more than 5000 years, Contemporary pharmacology in China began around 1930 Ephedra - Dr K.K. Chen, paved the way for subsequent exploration in sympathomimetics. The Chinese Society of Physiology in 1926 2. Growth(1949–1985) Experienced a steady growth since 1949 Major discoveries in this period include sodium dimer-captosuccinnate, antitumor agents such as camptothecins, hydroxycamptothecins Treatment of acute promyelocytic leukemia with all-trans retinoic acid was another original discovery made in China Then came period of ‘ cultural revolution’ Chinese Pharmacological Society was established in 1979 and started to publish a journal in English – Acta Pharmacologica Sinica in 1980.
- 7. The society finally joined the International Union of Pharmacology (IUPHAR) in 1985, signaling China’s entry onto the international stage of pharmacology Expansion (1986–present) Since China joined the World Trade Organization (WTO) in 2001, funding for scientific research has risen steadily. National Centre for Drug Screening (NCDS) along with a number of other Recently via the foundation of the Chinese National Compound Library (CNCL) HAVE approx.1.3 million sample collections Outlook Although pharmacological studies on TCM will continue to be a focal point, strong emphases will be directed towards basic and original research ‘Lead Project’ on personalized medicine at the Chinese Academy of Sciences
- 8. Computational methods for drug design and discovery: focus on China Drug discovery in China Taking the structure-based drug design (SBDD) as an example, the publication of scientific papers from China during 2006 to 2010 ranked fifth (citation ranking is seventh) Among Asian countries, China ranked the top in both the number of publications and citations Computational strategies and techniques in drug design Pharmacophore modelling Measures to what extent a query molecule possesses the spatial arrangement of features essential for protein–ligand interaction, requires less time to screen a ligand than docking Reverse docking Identifying targets is the first key step, One of the computational approaches demonstrated to be efficient and cost effective in target identification The identified protein ‘hit’ can then serve as a potential candidate
- 10. Drug repositioning To boost the productivity of the current drug design process “new uses for an existing drug”. Besides classical target- and ligand-based computational methods, in recent years, many drug repositioning approaches based on systems biology have been developed. For ex.- network-based inference (NBI) method which used the topology similarity of the ligand–target network to prioritize new targets for a given drug, or vice versa. There are some databases that focus on the biological actions of drugs, for example, DrugBank, TTD , SuperTarget and MATADOR , STITCH (search tool for interactions of chemicals) Protein–ligand interaction Molecular docking plays a central role in predicting protein–ligand interactions, which has been extensively used for drug hit discovery and lead optimization
- 11. Virtual screening and lead optimization Hit identification also VS. A useful VS tool named SHAFTS (SHApe FeaTure Similari- ty) , which is a hybrid approach comparing both molecular shape and pharmacophore features 1. Pharmacophore-based VS is an established in silico tool that has resulted in the identification of many active compounds in drug discovery programs. 2. . Shape-based VS is another useful tool for searching for novel lead compounds 3. Commercial chemical libraries for high-throughput screening (HTS) are primary sources for hit identification In silico prediction of ADME/T properties These properties to the failure rates of drug discovery and the resultant mounting cost of bringing a new drug to the market Web-based SOM prediction service, provides medicinal chemists a visual and easy-to-use interface for addressing some metabolism-related problems.
- 12. Successful applications of CDDD Cases of drug target identification A natural product isolated from ‘Ceratostigma willmottianum’ was found effective in inhibiting the bacterium- H.Pylori Finding using Tar- FisDock includes revealing the mechanism of gingerol (in control n management of cancer) Another case study of in silico target prediction include fibroblast growth factor receptors (FGFRs), as targets for the treatment of various human cancers. Qian and colleagues used the reverse pharmacophore mapping approach PharmMapper to identify target candidates for an active compound that they previously synthesized and showed great in vitro antiproliferative effects Cases of hit discovery Molecular docking is one of the most widely employed New Delhi metallo-b-lactamase-1 (NDM-1) has recently attracted extensive attention for its rapid dissemination and resistance to
- 13. almost all known b-lactam antibiotics, Shen et al provided useful clues for the rational design of effective NDM-1 inhibitors Another distinguished contribution made by Chinese researchers is the identification of a new indication for an old drug cinanserin, a well- characterized serotonin antagonist Concluding remarks CDDD is a multidisciplinary technology SPEEDS UP DD The philosophy embodied in CDDD is shifting from ‘one gene, one drug, and one disease’ to ‘multicomponent therapeutics, network targets
- 14. Regulation of the Hippo pathway and implications for anticancer drug development Hippo tumor suppressor pathway also known as the Salvador/Warts/Hippo (SWH) pathway The Hippo– YAP/TAZ pathway was linked to diverse G- protein coupled receptor (GPCR) ligands and receptor signalling Role in organ size regulation and tumorigenesis Composition of hippo pathway In mammals, the core components of the Hippo pathway consist of serine/threonine kinases MST1/2, Lats1/2 and their adaptor proteins Sav1 and Mob MOBKL1A and MOBKL1B
- 15. Control by the Hippo pathway implicated in diverse cellular and tissue properties which includes- apicobasal polarity, • Cell- cell adhesion1 • Contact inhibition2 • Planer cell polarity3 • Mechanotransduction4 • Various diffusible signals5
- 16. Dysregulation: caused by gene mutation or aberrant expression, promotes cell proliferation and tumorigenesis
- 17. Recent advances related with hippo pathway 1. Recent reports show that Ga12/13-, Gaq/11-, Gai/o-coupled GPCRs activate YAP/TAZ and promote nuclear translocation 2. Gas-coupled GPCRs suppress YAP/TAZ activity 3. Also, dobutamine- a Ga-coupled b-adrenergic agonist, inhibits YAP-dependent gene transcription 4. Epinephrine and glucagon also inhibit YAP/TAZ activity by activation of Gas–cAMP–protein kinase A (PKA)–Lats1/2 5. Growth factor signalling: TGF-b IGF EGF Interact with several effectors of those pathways such as b-catenin and Smad proteins WHERE AS, impact on human cancer in which YAP/TAZ are highly expressed
- 18. Structural and energetic analysis of drug inhibition of the influenzaA M2 proton channel TypeA influenza virus matrix protein 2 (A M2) highly selective proton channel in the viral envelope Role in viral infection and replication- a target of anti-influenza drugs Drugs acting through these channels Amantadine Rimantadine Problem- these drugs have met with resistance! M2 channel Homotetramer comprising four 97- residue transmembrane (TM) peptides TheTM domain is composed of four parallel a helices
- 19. Drug design targeting drug-resistant mutant M2 channels Involves following approaches: 1. Pharmacophores of adamantane-based drugs includes one large hydrophobic adamantane group and a polar group, mimicking the structures of amantadine and rimantadine 2. Designing drugs with novel scaffolds M2 channel is structurally flexible, can accommodate hydrophobic groups with different shapes and sizes Using different types of hydrophobic groups 3. Drug design targeting the S31N mutant S31N mutation introduces large polar Asn31 side chains and abolishes the hydrophobic interactions Accomplished by Ammonium group placed with variations
- 20. From obesityto substance abuse: therapeutic opportunities for 5- HT2C receptor agonists 5-HT system Have established impact on drug therapy arena of CNS acting drugs In 2000 top five selling central nervous system (CNS) drugs had a modulatory effect on 5-HT function as a recognized part of their mechanism of action In obesity control of ingestive behavior, modulation of behavioral effects Lorcaserin (Lorqess) – was approved by the FDA in 2012 for the treatment of obesity alter various behaviors and underlying neurobiological systems relevant to drug abuse and addiction likely act directly on paraventricular nucleus to alter metabolic aspects of feeding
- 21. Characteristics of the 5-HT2C receptor Only known G protein-coupled receptor (GPCR) that undergoes RNA editing Differing behavioral phenotypes have also been described in transgenic mice expressing specific isoforms of 5-HT2C The ability of fenfluramine and sibutramine to reduce food intake partly depends on 5-HT2C receptors Behavioral effects of drugs of abuse Most drugs of abuse directly or indirectly enhance DA ‘Ro60-0175’ reduced reinstatement of cocaine-seeking behavior (antagonist M100907 reduces ) reduced attenuated nicotine-induced locomotion, nicotine self- administration
- 22. reduced impulsivity found experimentally in rats Psychoactive effects including ‘detached’ ‘spaced out’, ‘floating’ - Treating nicotine dependence with 5-HT2C receptor agonists may be a more realistic therapeutic objective Concluding remarks Drug abuse and addiction is a potential therapeutic target for 5-HT2C receptor agonists, and to further suggest that the mechanisms that contribute to antiaddictive property may similarly contribute to efficacy against obesity Opportunities to evaluate lorcaserin for smoking cessation and psychostimulant abuse
Editor's Notes
- XTEN is a proprietary recombinant polypeptide that, when genetically fused to a therapeutic payload of interest, extends the in vivo half-life of these peptides and proteins in a tunable manner………………….. . Codon optimization is a technique to maximize the protein expression in living organism by increasing the translational efficiency of gene of interest by transforming DNA sequence of nucleotides of one species into DNA sequence of nucleotides of another species
- (site of metabolism)
- New Delhi Metallo-beta-lactamase-1 (NDM-1)[1] is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family, which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because infections caused by them are difficult to treat. Such bacteria are usually susceptible only topolymyxins and tigecycline.[2] NDM-1 was first detected in a Klebsiella pneumoniae isolate from a Swedish patient of Indian origin in 2008. It was later detected in bacteria in India, Pakistan, the United Kingdom, the United States,[3] Canada,[4] and Japan.[5] The most common bacteria that make this enzyme are Gram-negative such as Escherichia coli and Klebsiella pneumoniae, but the gene for NDM-1 can spread from one strain of bacteria to another by horizontal gene transf 2010..
- Hippo signaling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self renewal. In addition, dysregulation of the Hippo pathway contributes to cancer development - See more at: http://www.cellsignal.com/contents/science-pathway-research-stem-cell-markers/hippo-signaling-pathway/pathways-hippo#sthash.Je5bAyPF.dpuf
- These methods have led to the successful designs of effec-tive drug candidates for several M2 mutants and show great promise
- recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes
- RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within a RNA molecule after it has been generated by RNA polymerase. RNA editing is relatively rare, and common forms of RNA processing (e.g. splicing, 5'-capping and 3'-polyadenylation) are not usually included as editing. Editing events may include the insertion, deletion, and base substitution of nucleotides within the edited RNA molecule.