Background: Gonadotropin-Releasing Hormone (GnRH) is a key element in sexual maturation and regulation of the reproductive cycle in the human organism. GnRH interacts with the pituitary cells through the activation of the Gonadotropin Releasing Hormone Receptors (GnRHR). Any impairments/dysfunctions of the GnRH-GnRHR complex lead to the development of various cancer types and disorders. Furthermore, the identification of GnRHR as a potential drug target has led to the development of agonist and antagonist molecules implemented in various treatment protocols. The development of these drugs was based on the information derived from the functional studies of GnRH and GnRHR.Objective: This review aims at shedding light on the versatile function of GnRH and GnRH receptor and offers an apprehensive summary regarding the development of different agonists, antagonists and non-peptide GnRH analogues.Conclusion: The information derived from these studies can enhance our understanding of the GnRH-GnRHR versatile nature and offer valuable insight into the design of new more potent molecules.

In this report, amide-linked cyclic peptide analogues of the 87–99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP_87–99 with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP_72–85-induced EAE in Lewis rats. The Lys⁹¹ and Pro⁹⁶ of MBP_87–99 are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91–99)[Ala⁹⁶]MBP_87–99, cyclo(87–99)[Ala^91,96]MBP_87–99 and cyclo(87–99)[Arg⁹¹, Ala⁹⁶]MBP_87–99, but not wild-type linear MBP_87–99, strongly inhibited MBP_72–85-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87–99)[Arg⁹¹, Ala⁹⁶]MBP_87–99 was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction.

Gonadotropin-releasing hormone (GnRH) is pivotal in regulating human reproduction and fertility through its specific receptors. Among these, gonadotropin-releasing hormone receptor type I (GnRHR I), which is a member of the G-protein-coupled receptor family, is expressed on the surface of both healthy and malignant cells. Its presence in cancer cells has positioned this receptor as a primary target for the development of novel anti-cancer agents. Moreover, the extensive regulatory functions of GnRH have underscored decapeptide as a prominent vehicle for targeted drug delivery, which is accomplished through the design of appropriate conjugates. On this basis, a rationally designed series of anthraquinone/mitoxantrone–GnRH conjugates (con1–con8) has been synthesized herein. Their in vitro binding affinities range from 0.06 to 3.42 nM, with six of them (con2–con7) demonstrating higher affinities for GnRH than the established drug leuprolide (0.64 nM). Among the mitoxantrone based GnRH conjugates, con3 and con7 show the highest affinities at 0.07 and 0.06 nM, respectively, while the disulfide bond present in the conjugates is found to be readily reduced by the thioredoxin (Trx) system. These findings are promising for further pharmacological evaluation of the synthesized conjugates with the prospect of performing future clinical studies.

Mannan (polysaccharide) conjugated with a myelin oligodendrocyte glycoprotein (MOG) peptide, namely (KG)₅MOG_35–55, represents a potent and promising new approach for the immunotherapy of Multiple Sclerosis (MS). The MOG_35–55 epitope conjugated with the oxidized form of mannan (poly-mannose) via a (KG)₅ linker was found to inhibit the symptoms of MOG_35–55-induced experimental autoimmune encephalomyelitis (EAE) in mice using prophylactic and therapeutic vaccinated protocols. Deamidation is a common modification in peptide and protein sequences, especially for Gln and Asn residues. In this study, the structural solution motif of deaminated peptides and their functional effects in an animal model for MS were explored. Several peptides based on the MOG_35–55 epitope have been synthesized in which the Asn⁵³ was replaced with Ala, Asp, or isoAsp. Our results demonstrate that the synthesized MOG peptides were formed to the deaminated products in basic conditions, and the Asn⁵³ was mainly modified to Asp. Moreover, both peptides (wild type and deaminated derivative) conjugated with mannan (from Saccharomyces cerevisiae) independently inhibited the development of neurological symptoms and inflammatory demyelinating spinal cord lesions in MOG_35–55-induced EAE. To conclude, mannan conjugated with a deamidated product did not affect the efficacy of the parent peptide.