Peptide analogs

Abstract

Analogs for CLR / RAMP receptor ligands are provided that have agonist, superagonist, antagonist, super-antagonist, or multiple receptor modulatng activity. The analogs can be selective for one or more CLR / RAMP receptors, or can be pan-specific for multiple G protein-coupled receptors.

Description

CROSS REFERENCE[0001]This application claims benefit of U.S. Provisional Patent Application No. 62 / 527,680, filed Jun. 30, 2017, which application is incorporated herein by reference in its entirety.[0002]The present embodiments relate to superagonists and superantagonists of the adrenomedullin (ADM) / calcitonin gene-related peptide (CGRP) / intermedin (adrenomedullin 2, IMD) family of peptide hormones and therapeutic uses thereof. Also provided are multiple receptor ligands (MRLs) that regulate CLR / RAMP receptors, and a second G protein-coupled receptor (GPCR), including somatostatin receptors, neurotensin receptors, apelin receptor, bradykinin receptors, and type 1 angiotensin II receptor.BACKGROUND[0003]G protein-coupled receptors (GPCRs) are cell surface receptors and represent one of the largest protein families in the human genome. Based on phylogenetic criteria, the large superfamily of human GPCRs can be subdivided into the five main subfamilies: Glutamate, Rhodopsin, Adhesion,...

AI Technical Summary

Benefits of technology

The patent describes how certain modifications to certain peptides can make them more effective or efficient in regulating certain receptors in the body. By adding or modifying certain parts of the peptides, researchers have been able to create new agents that can target multiple receptors and prevent or treat various diseases. These modified peptides can also help prevent side effects and achieve specific targeting in the body. Overall, this patent shows how researchers have been able to create more powerful and specific tools for regulating receptors in the body for therapeutic purposes.

Problems solved by technology

However, select small molecule CGRP antagonist such as MK-3207 has been associated with asymptomatic liver test abnormalities in some patients.

While a number of CGRP receptor peptide antagonists have been shown to effectively compete with CGRP in vitro, these antagonists have not performed as well in in vivo models of migraine-like pathologies due to low bioactivities.

However, existing therapeutic candidates are associated with efficacy or safety concerns.

Second, the small molecule CLR / RAMP1 receptor antagonists suffer liver toxicity in humans.

Fourth, the antibodies have low volume of distribution when compared to small molecules and peptides, and have limited access to CLR / RAMP receptors in the central nervous system.

However, due to limited potency of the agonist and the short half-life, pharmacological effect is inadequate.

Despite these advances, physicians are having difficulties to achieve controlled blood pressure in patients with resistant hypertension (RHTN).

In fact, there is scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressure in RHTN patients.

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