Engineering endomorphin drugs: state of the art

Abstract

Importance of the field Although EM-1 (H-Tyr-Pro-Phe-Trp-NH2) and EM-2 (H-Tyr-Pro-Phe-Phe-NH2) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties suitable for application to health related topics. Areas covered in this review This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. What the reader will gain While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimental delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability, formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. Take home message Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.

Glial dysfunction and persistent neuropathic postsurgical pain

“…It has also been found in inflammatory tissue, implying that it may interact with immune cells. Astrocytes possess -opioid receptors, and endomorphins may play a role in the control of neuroinflammatory activity [99,100]. Morphine activates the -opioid receptor, which in turn activates the second messenger protein G i/o .…”

Evaluation of cellular responses for a chimeric HBsAg-HCV core DNA vaccine in BALB/c mice

“…[ 2 ] In this context, potential of DNA vaccination for induction of specific cellular immune responses made it attractive for development of HCV vaccines if the amount of the responses elicited by such vaccination strategy could be enhanced. [ 3 4 ] Accordingly, results of the preceding attempts to utilize HCVcp for immunization (which has been considered as a superior immunogenic antigen) indicated that HCVcp is a rather weak immunogen when used in the context of DNA vaccine. [ 3 4 21 22 ] To overcome this shortcoming, formulations based on a mixture of DNA vaccine harboring HCVcp together with recombinant HCV core particles[ 6 ] or coadministration of IL-23 and GM-CSF were considered to enhance the immune responses toward HCV-core DNA vaccination regimen.…”

“…During prior years, great attempts and diverse strategies were employed to provide efficient vaccines against HCV infection by using different HCV antigens in various formulations and modalities such as recombinant protein (subunit), plasmid DNA, peptide, live vector-based and epitopic/polytopic vaccines. [ 2 3 ] Accumulated data from these previous studies suggested that cellular responses including HCV-specific cytotoxic T-lymphocytes (CTL) play a significant role in recovery of infected persons. In effect, CD8+ cell responses to viral epitopes accompanied with CD4+ helper activities and secretion of the Th1-type cytokines is shown to be efficient in HCV elimination, while the role of antibodies seems to be limited.…”

“…[ 2 ] Accordingly, among different vaccine modalities, DNA vaccination against HCV was of interest because of possibility of inducing strong and specific cellular immune responses by DNA immunization. [ 3 4 ] Induction of weak immune responses by DNA immunization was, however, the major shortcoming of such vaccines, which has been conquered by several approaches[ 3 ] like coadministration of immunological adjuvant such as IL-23 and GM-CSF[ 5 ] or DNA and recombinant protein vaccine. [ 6 ] More recently, fusion of virus-like particle (VLP)-forming elements (like hepatitis B surface antigen; HBsAg), which encode viral structural proteins capable of assembling into particulate repeated arrays, are considered as a promising approach for the efficient delivery of antigenic targets.…”

“…[ 2 17 ] In this context, truncated form of HCVcp representing the first 120 N-terminal residues (hydrophilic region), which contains both nuclear localization signals (NLS)[ 18 ] and conserved epitopes for cellular and CTL responses was considered for formulation of a number of HCV vaccine candidates. [ 2 19 20 ] Results of these previous studies, however, indicated that (as could be anticipated) HCVcp is a rather weak immunogen when used as a DNA vaccine (compared with adjuvanted subunit vaccines),[ 3 4 21 22 ] and therefore sounded for the need of improvements in the formulation of HCVcp-based DNA vaccine modalities.…”