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strategies that introduces chemical modifications into peptides containing natural amino acids that limits proteolytic degradation, and using alternative routes of administration(injection) [49,51]. Keeping aside these shortcomings which we have almost overcome it should be noted peptides have the potential to penetrate further into tissues owing to their smaller size. Moreover, therapeutic peptides, even synthetic ones, are generally less immunogenic than recombinant proteins and antibodies [51,52]. Peptides have other advantages over proteins and antibodies asdrug candidates, including lower manufacturing costs, 15-50 higher activity per unit mass, greater stability (long storage at room temperature a), and better organ or tumour penetration. Therapeutic peptides also offer several advantages over small organic molecules that make up traditional medicines. The first advantage is that often representing the smallest functional part of a protein, they offer greater efficacy, selectivity and specificity than small organic molecules. A second advantage is that the degradation products of peptides are amino acids, which minimizing the risks of systemic toxicity. Third, because of their short half-life, few peptides accumulate in tissues (reduction of risks of complications caused by their metabolites). As result of these advantages, large number of therapeutic peptides and proteins have mushroomed over years [51] . Table 3 provides brief overview of some important proteins and peptides that currently used as drugs and table 4 summarizes some of important peptides and proteins that are currently in clinical trials. Protein/peptide Peptides • Corticorelin • Lisinopril • Exenatide • Human calcitonin • Epitifibatide • Icatibant acetate • Pramlintide • Buserelin • Goserelin • Octreotide Proteins Growth hormone Human serum albumin Lactoferrin Hirudin IgG/IgM/IgA Hepatitis B virus envelope protein Rabies virus antigen Norwalk virus antigen Protein C Collagen Erythropoietin Indications Diagnosis of cushings syndrome Hypertension Controls type 2 diabetes mellitus Pagets disease, postmenopausal osteoporosis Acute coronary syndrome Hereditary angioedema Both type 1 and type 2 diabetes Prostrate cancer Breast cancer Acromegaly Growth hormone deficiency Livea cirrhosis, burns Antimicrobial activity Thrombin inhibitor Therapeutic Vaccine Vaccine (edible) Vaccine Anti coagulant Therapeutic/cosmetic Anemia Table 3: Important protein and peptide that have reached American European union or Japanese market. Product Type Tested for Anti IL-13 antibody Antibody Therapy, also used for assays, flowcytometry Adnectin High affinity Ig-like protein Enginnered domain of fibronectin, used as bispecific antibody Pegdinetanib Antagonist of growth factor receptor Anti cancer drug gp 100 Protein Vaccine for melanoma HPV – 16/E7 Protein Vaccine for cervical cancer Vedolizumab Antibody Crohn disease Trastuzumab Antibody Brest cancer Corticorelin acetate Peptide, corticotrophin releasing factor Anti tumor activity Bicyclic Peptides Table 4: List of some important proteins and peptides that are currently in clinical and preclinical trials. The poor tissue penetration, difficult and expensive procedure for chemical synthesis, and the need for application by injection led scientists to wonder about other alternatives such as smaller protein scaffolds as alternatives to antibodies. Polycyclic peptides could deliver better tissue penetration, higher activity per mass and a wider choice of administration routes than antibodies. Christian Heinis who was studying, protein-based scaffolds discovered that the bicyclic peptide structure could interact with the protein much like antibodies i.e, they act as small, adaptable antibodies that can bind to antigens via their surface loops. Such peptides could potentially be chemically synthesised, and at least have equivalent binding qualities to antibodies [53]. In 2012, Winter and Heinis formed a company Bicycle Therapeutics, which is based in Cambridge, UK. The prime focus of this company is on medical conditions for which the use of bicyclic peptides promises advantages over both small molecules and monoclonal antibodies. They have recently engineered potent bicyclic peptide (Figure 10) inhibitors that specifically block human kallikrein and murine proteases, but not other proteases. The high selectivity ensures that drug (peptide) binds to target only and to multitude of other binding sites as the nonspecific binding can often lead to toxicity [53]. Our increasing understanding of biological sciences will continue to define new targets for immune therapies and advancements of protein sciences will provide us with vision and tools for a safer and effective therapy. Hopefully, some of the recent breakthroughs in protein biology will advance science, accelerate technology and discoveries, affecting varied range of diseases. We all hope that these discoveries will flourish and provide hope, enrich our lives, create dreams and help us rejoice in this exciting period of scientific discovery. OMICS Group eBooks 013
Coming years will witness increasing number of exciting therapeutic trials. We will also encounter undesirable surprises along the way but with the zeal and success seen in past few years we can be sure that era of pathogenesis based therapy is there in not so distant future. Figure 10: Schematic representation of bicyclic protein. Acknowledgement The authors wishes to thank Dr. Haseeb Ahsan , for critically reading the manuscript and giving helpful suggestions. References 1. Rawlins MD (2004) Cutting the cost of drug development? Nat Rev Drug Discov 3: 360-364. 2. Di Masi J A and Grabowski H G (2007) The cost of biopharmaceutical R&D is biotech different Manag. Decis. Econ 28: 469–479. 3. http://www.prweb.com/releases/2013-monoclonal-antibody/industry analysis-report/ 4. zur Hausen H (1987) Papillomaviruses in human cancer. Appl Pathol 5: 19-24. 5. Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, et al. (2007) Prevalence of HPV infection among females in the United States. JAMA 297: 813-819. 6. Ramet J, van Esso D, Meszner Z; European Academy of Paediatrics Scientific Working Group on Vaccination (2011) Position paper--HPV and the primary prevention of cancer; improving vaccine uptake by paediatricians. Eur J Pediatr 170: 309-321. 7. Mallik H I, Khan F H, Ahsan H (2013) Human Papilloma virus- Current status and issues of vaccination. Archives of Virology. In press 8. Garcea RL, Chen X (2007) Papilloma virus structure and assembly. In: R L Garcea, D. DiMaio (eds.). The papilloma viruses. Springer, New York, USA. 9. Danos O, Engel LW, Chen EY, Yaniv M, Howley PM (1983) Comparative analysis of the human type 1a and bovine type 1 papillomavirus genomes. J Virol 46: 557-566. 10. Moody CA, Laimins LA (2010) Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10: 550-560. 11. Grabowska AK, Riemer AB (2012) The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J 6: 249-256. 12. Ashrafi GH, Brown DR, Fife KH, Campo MS (2006) Down-regulation of MHC class I is a property common to papillomavirus E5 proteins. Virus Res 120: 208-211. 13. Reiter PL, McRee AL, Kadis JA, Brewer NT (2011) HPV vaccine and adolescent males. Vaccine 29: 5595-5602. 14. Fraser C, Tomassini JE, Xi L, Golm G, Watson M, et al. (2007) Modeling the long-term antibody response of a human papillomavirus (HPV) virus-like particle (VLP) type 16 prophylactic vaccine. Vaccine 25: 4324-4333. 15. Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, et al. (2007) Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 369: 1693-1702. 16. Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, et al. (2007) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papilloma virus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 369: 2161-2170. 17. Mello MM, Abiola S, Colgrove J (2012) Pharmaceutical companies’ role in state vaccination policymaking: the case of human papillomavirus vaccination. Am J Public Health 102: 893-898. 18. Beutner KR, Ferenczy A (1997) Therapeutic approaches to genital warts. Am J Med 102: 28-37. 19. Alexander R, Hurt AC, Lamb D, Wong FY, Hampson AW, et al. (2005) A comparison of a rapid test for influenza with laboratory-based diagnosis in a paediatric population. Commun Dis Intell Q Rep 29: 272-276. 20. Khan FH (2009) The Elements of immunology. Pearson Education India, India. 21. Morrison SL, Johnson MJ, Herzenberg LA, Oi VT (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A 81: 6851-6855. 22. Jones PT, Dear PH, Foote J, Neuberger MS, Winter G (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321: 522-525. 23. Cheung NV (2008) Therapeutic antibodies and immunologic conjugates. In: Abeloff, Doroshow, Tepper, Armitage, Niederhuber, et al. (eds.). Abeloff’s Clinical Oncology. (4thedn), Churchill Livingstone, Philadelphia, USA. 24. Hudson PJ, Souriau C (2003) Engineered antibodies. Nat Med 9: 129-134. 25. Hudis CA (2007) Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 357: 39-51. OMICS Group eBooks 014
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