Peptide and protein based pharmaceuticals

Abstract

It is predicted that in the 21st century there will be more and more new drug investments that violates the Lipinski's “rule-of-five”. Among them, peptides have received increased interest in the current drug therapies. Advantages of peptide-based pharmaceuticals are the high potency and selectivity as well as their low accumulation in tissues; thus, they have potentially lower toxicity than the small drug molecules. Furthermore, the high chemical and biological diversity of peptides provide a broad range of targets, which could represent a basis for personalized medication. Currently, there are more than 70 approved peptide drugs on the market, generating an annual sale close to USD 20 billion in 2012. About half of them are presented in this chapter, which ones are used for the treatment of diabetes, cancers, multiple sclerosis, HIV, hereditary angioedema, respiratory distress syndrome, prevention of thrombosis or relief pain. Next to the structures of the peptide-based pharmaceuticals, their biological activity on the mentioned diseases will be shortly discussed. An outlook for the new peptide-based drug development indicates high perspectives of this area.

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

“…Interestingly, Ser at position 4 could be replaced by Lys or acetylated Lys [ 147 ]. It is worth mentioning that the Ser in GnRH agonist and antagonist analogs are rarely modified [ 148 ]. The incorporation of Lys or Lys(Ac) in position 4 of GnRH-III increased the antitumor activity of the conjugate GnRH-III(Dau=Aoa).…”

Recent advancements in the hormonal stimulation of ovulation in swine

“…The discovery and elucidation of the structure of GnRH in the 1970s lead to the synthesis of the decapeptide its agonists and antagonists. 73 Modification of GnRH with substitution of an inactive amino acid at position 6 was used to decrease the rate of degradation by endogenous peptidases, while substitution or deletion in amino acid position 10 increased receptor affinity, with the combined effect to increase potency 10–200 times. 27 However, in humans and some other species, the intent of administration of GnRH with high potency is often to inhibit gonadotropin release in the long-term, through blocking or downregulation of GnRH receptors.…”

“… 81 Alternative methods for GnRH administration have been available for many years in humans for medical treatment and control of reproduction and have included injection, nasal spray, slow release capsules, and intravaginal gels. 71 , 73 , 82 Route of administration has been shown to alter the effective dose, and rabbits given a GnRH analog in the semen for intravaginal absorption, required a 15% increase for induction of ovulation through the vaginal mucosa. 11 In pigs, intravaginal administration of a GnRH analog (triptorelin) was shown to induce an LH surge within 4–16 hours and ovulation within 44 hours following deposition, and which could be altered by changing the viscosity of the carrier gel formulation.…”

Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification

“…Both peptide-based pharmaceutics were approved by the Food and Drug Administration (FDA) at the beginning of this century [10,11]. Cetrorelix acetate was the first GnRH antagonist on the market and is used to prevent premature luteinizing hormone (LH) surges in women undergoing controlled ovarian stimulation, whereas triptorelin pamoate received approval for the palliative treatment of advanced prostate cancer [10,11,12]. These potent GnRH analogs bind like the natural peptide hormone GnRH-I (<EHWSYGLRPG-NH 2 ; <E is pyroglutamic acid) to pituitary GnRH receptor (GnRH-R) on gonadotrophs [13,14].…”