The Beijer Laboratory for Drug Discovery

PROJECT TITLE: Peptidemimetics (Peptidhärmande läkemedel)

DIRECTOR: Prof Anders Hallberg, DEPUTY DIRECTOR: Prof Mats Larhed

ORGANIZATION: The Beijer Laboratory for Drug Discovery consists of two integrated parts: A medicinal chemistry node at the Department of Medicinal Chemistry and a pharmacology node at the Department of Pharmaceutical Biosciences.

MAIN OBJECTIVE: To utilize short bioactive endogenous peptides as starting points in design processes and create drug-like substances (peptidemimetics) with potential use in clinic. The goal is to make substances that mimic the positive biological effects of peptides but contrary to the peptides exhibit high stability and bioavailability in vivo.

BACKGROUND: Peptides, and bioactive fragments derived from peptides are not in general suitable as drugs since they are not bioavailable after oral administration and are not metabolically stable. Thus, the pharmacokinetic profiles of small peptides are far from optimal. Peptides and their fragments, however, can sometimes serve as starting points in design processes aimed at identifying drug-like substances that interact with their receptors. New selective, metabolically stable drug-like agonists (peptidemimetics) and antagonists and in particular those that are able to cross the blood–brain barrier (BBB) are constantly required.

The octapeptide angiotensin II (Ang II) and its bioactive hexapeptide fragment angiotensin IV (Ang IV) are applied as model peptides. The Beijer Laboratory for Drug Discovery is engaged in four angiotensin projects. Two of those subprojects are primarily addressed at present and are briefly described below.

  • AT2 agonists (idiopathic pulmonary fibrosis)
  • AT2 antagonists (neuropathic pain)
  • Dual AT1R/AT2R ligands (renoprotection)
  • Ang IV mimetics (cognition)

Angiotensin II AT2 receptor antagonists

MEDICAL NEED: There is an unmet medical need for efficient treatment of neuropathic pain. Current therapy needs to be improved due to dose-limiting side effects and the lack of response in many patients. It is estimated that only one in four patients with neuropathic pain experiences over 50% pain relief. Neuropathic pain is defined as pain arising as direct consequence of a lesion or disease affecting the somatosensory system. The causes of neuropathic pain are diverse and include a) diabetes (diabetic neuropathy), b) viruses (e.g. post herpetic neuralgia; PHN) c) cancer or its treatment with therapy agents (e.g. chemotherapy induced neuropathy), and d) nerve trauma (peripheral nerve injury induced neuropathy).

PROJECT RATIONAL: Angiotensin II induces neuronal excitability through stimulation of the angiotensin II, type 2 receptor (AT2R). Hyperexcitability of dorsal root ganglion neurons is a key mechanism that contributes to neuropathic pain. The new AT2R antagonists, anticipated to act via peripheral mechanisms is expected to be devoid of the severe CNS related adverse effects encountered with current pharmacotherapy, e.g. with the GABA analogue pregabalin.

AIM: To use the molecular structure of angiotensin II as starting point and design, synthesize and develop selective, potent and bioavailable peptidemimetic AT2R antagonists for the treatment of neuropathic pain, (primarily diabetic neuropathy, post herpetic pain and common neuropathic pain from herniated disc) and to take advantage of our experience from drug discovery programs in the AT2R area. To validate the AT2R as a new target for analgesics.

Angiotensin IV mimetics

MEDICAL NEED:  It is estimated that as high as 20-25% of the populations over 80 years of age suffer from cognitive impairment or age-related cognitive decline. Alzheimer’s disease (AD) accounts for 60-70% of the cases of dementia. There are more than 100 000 people in Sweden with Alzheimer’s disease. Consequently, there is a strong demand for efficient new chemical entities for the treatment of the cognitive decline associated with AD, brain trauma, and cerebral ischemia since the data from the clinical evaluations of the drugs used today have been mostly disappointing. In addition, the rate of failure in clinic of new drug candidates is also high and therefore new avenues, relying on new and alternative mechanisms of action have to be explored constantly.

PROJECT RATIONAL: It is reported that intracerebroventricular (icv) injection of the hexapeptide angiotensin IV (Ang IV), a degradation fragment of angiotensin II, improves memory and learning in rat and mice as deduced from several studies in a large variety of animal models. High densities of binding sites for Ang IV were found in areas of the brain associated with cognitive, sensory and motor functions, including the hippocampus. The Ang IV receptor was identified as insulin-regulated aminopeptidase (IRAP), a single-spanning transmembrane zinc-metallopeptidase that belongs to the M1 family of aminopeptidases. Ang IV acts as an inhibitor of IRAP.

AIM: To use the molecular structure of angiotensin IV as starting point and develop potent unique peptidomimetics that enter the brain after oral administration and that inhibit insulin-regulated aminopeptidase (IRAP) as a new class of cognitive enhancers for use in the therapy of Alzheimer’s disease.

BEIJER SCHOLARS 2014-2018:

Pharm Dr Jonas Sävmarker, Department of Medicinal Chemistry

Pharm Dr Mathias Hallberg, Department of Pharmaceutical Biosciences.