Senior Research Scientist, Chemistry and Biochemistry-Sci

Lajos Szabo

Druggable Formulation for Mu/Delta Opioid Antagonist for Enhancing Pain Therapy and Treatment of Opioid WithdrawalThis invention provides compositions and method of pain treatment using a mu/delta opioid receptor heterodimer (MDOR) antagonist which has improved druggability by nanoformulation and/or glycosylation to increase their bioavailability and efficacy. These modified antagonists and formulations provide for enhancement of opioid agonist therapy's antinociceptive effects, reduction of side effects or adverse effects of opioid agonist therapy, and reduced withdrawal symptoms. Proof-of-concept testing in animals has shown a significant increase in oxymorphone antinociception.  

Background:
Opioids continue to be widely used for pain treatment. However, constant opioid treatment is accompanied with serious undesirable effects including drowsiness and mental clouding, nausea and emesis, constipation and in many cases dependence and addiction. Continuous use of opioid therapy also develops analgesic tolerance and hyperalgesia in many patients. These unwanted effects significantly diminish the patients’ quality of life. The mechanisms for these side effects are still largely unclear.  However, one particular side effect, namely addiction, is a cause for great concern in pain treatment using opioids.

Prescription opioids can be highly addictive and are widely misused. It has been estimated that the total economic cost of opioid misuse in the United States is $78.5 billion per year. The opioid crisis has been exacerbated by over-prescription of opioid pain-relievers for the treatment of pain. Due at least in part due to over-prescription and additive nature of opioids, some who experience chronic pain may suffer undertreatment. In fact, in many parts of the developing world, access to opioids even for acute pain and/or cancer pain can be restricted due to concerns over addiction and overdose. Even in the United States, some patients can suffer from an undertreatment of pain. For example, patients with cognitive impairment and the elderly can be especially susceptible to the central nervous system effects of traditional opioids such as morphine and in some cases are not prescribed enough to meet their pain management needs.
Receptors do not only signal as single units, but can bind to each other to form dimers and oligomers that signal differently from single receptors. In earlier work, the inventors developed a selective antagonist compound for the mu/delta opioid receptor heterodimer (MDOR), and used this ligand to show that the MDOR acted as an opioid negative feedback loop, suppressing pain relief and enhancing side effects. Reversing this effect by treatment with this approach thus has promise in improving opioid pain relief and reducing side effects like withdrawal. However, the compound studied previously is a flexible peptide with poor metabolic stability and blood-brain barrier penetration. The inventors thus sought to improve druggability by developing analogues and formulation.

Applications:
· Pain treatment
· Opioid withdrawal

Advantages:
· Improve pain management
· Avoid withdrawal symptoms

Druggable Formulation for Mu/Delta Opioid Antagonist for Enhancing Pain Therapy and Treatment of Opioid Withdrawal

Micelles And Vesicles For The Delivery Of Glycopeptides

Neuroprotection via Glycosylated PACAP Analogues with Differentiated Selectivity toward PAC1 and VPAC1 > VPAC2Inventors at the University of Arizona have developed glycopeptide analogues of PACAP which exhibit selective PAC1 and/or VPAC1 receptor activity with a reduced VPAC2 receptor activity as compared to native PACAP, an endogenous peptide hormone associated with neuronal tissue repair.  Thus, these compounds have positive benefits of PAC1 and VPAC1 activation for neuroprotection and anti-inflammation, whilst reducing the activation of VPAC2, which is associated with neutrophil infiltration and edema.  Glycosylation provides for enhanced bioavailability to the brain.  These analogues have been designed with a shorter peptide length of about 20-25 amino acid residues in order to simplify the synthesis and development of these hormone-like drugs.

Background:
Neurodegenerative disorders continue to negatively impact the health and quality of life of millions of people worldwide. Many current therapeutic strategies involve only symptomatic alleviation, as there is a severe lack of treatments with the potential to halt or reverse disease progression. A plethora of studies have elucidated the molecular pathophysiology of various neurodegenerative diseases, revealing a complex interplay between neuronal apoptosis (oxidative stress, mitochondrial dysfunction, imbalances in ion homeostasis) and the inflammatory response in the brain.  Hyperactivation of microglia, the sentinel immune cells of the brain, results in the continual release of pro-inflammatory cytokines, which induces oxidative stress, mitochondrial dysfunction, imbalances in ion homeostasis, and eventual cell death.  It has been shown that these pro-apoptotic events induce further stimulation of hyperactive microglia (M1 state), establishing a continual cycle of neuronal cell death and neuroinflammation that promotes disease progression. Thus, one of the biggest challenges associated with treating neurodegenerative diseases is effectively addressing both the apoptotic and neuroinflammatory aspects simultaneously.

Endogenous pleiotropic peptide hormones are a representative class of compounds that may be able to address this critical problem. The pituitary adenylate cyclase activating peptide (PACAP) is one such endogenous peptide that has been shown to elicit neuroprotection and anti-inflammatory activity in animal models of Parkinson’s Disease (PD), ischemic stroke, Alzheimer’s Disease (AD), traumatic brain injury (TBI), and ethanol toxicity. It has been demonstrated that PACAP’s biological activities are elicited through three class B G-protein coupled receptors (GPCRs) known as PAC1, VPAC1, and VPAC2.  PACAP’s neuroprotective effects are mediated through PAC1, while vasodilatory and anti-inflammatory effects are modulated through VPAC1 and VPAC2, respectively. PACAP binds and activates PAC1, VPAC1, and VPAC2 with with high affinity, with roughly equal potency.  To reduce undesired side-effects, it may be desirable to pursue PACAP analogs having with a modified receptor profile.  Because PACAP has a non-selective receptor binding profile, there have been efforts to identify and produce PACAP analogues selective for PAC1.  While a little success has been attained, currently there is no known compound having a high PAC1 selectivity. In addition, the two isoforms, PACAP1-27 and PACAP1-38, are quite long in length and present a synthetic challenge, resulting in reduced yields and purity .  Therefore, there is a great need for PACAP analogs that are selective for PAC1 receptor.  There is also a need for PACAP analogs that have a shorter amino acid chains with selective PAC1 receptor agonist activity.

Applications:
· Ischemic stroke
· Traumatic brain injury
· Parkinson's Disease
· Alzheimer's Disease
· Other neurodegenerative diseases

Advantages:
· Selectivity for neuroprotection and antiflammation vs. side effects from VPAC2 receptor activation
· Glycosylation for effectiveness in crossing the blood-brain barrier
· Shorter peptide for ease of synthesis and work-up

Neuroprotection via Glycosylated PACAP Analogues with Differentiated Selectivity toward PAC1 and VPAC1 > VPAC2

Ang-(1-7) Derivative Oligopeptides and Methods for Using and Producing the Same

ANG(1-7) Derivative Oligopeptides And Methods For Using And Producing The Same

ANG-(1-7) Derivative Oligopeptides for the Treatment of Pain and Other Indications

ANG-(1-7) Derivative Oligopeptides for the Treatment of Pain

Novel Peptides Bioavailable to the Brain for Non-Opioid Pain Relief and/or Addiction TreatmentInventors at the University of Arizona have developed oxytocin analogues which have high potency, are designed to be more stable compared to the native oxytocin hormone (an endogenous peptide which inhibits pain and promotes social connection), have very high selectivity for oxytocin receptors, and are bioavailable for brain therapeutics. These druggable compounds may be further developed for use as non-opioid pain relief, social anxiety, anti-addiction, or post-traumatic stress disorder.

Background:
Opioid drugs like morphine and Oxycontin® are considered to be the gold standard for managing moderate-to-severe pain, and are often used to treat chronic pain as well. Unfortunately, these drugs are plagued with undesired side effects, particularly respiratory depression, GI effects, euphoria and sedation, and the use of these drugs can lead to opioid use disorder (OUD) and fatal overdose. Prescription rates and subsequent addiction, abuse, and hospital admissions for overdose have soared in the past 20 years for opioid drugs, with fentanyl-related abuse and overdose in particular skyrocketing since 2012. Many strategies have been developed to generate efficacious opioids with reduced addiction potential, such as biased ligands, multifunctional ligands, or endogenous peptide derivatives, but none have yet been translated to clinical use. This unsolved limitation of opioids illustrates the great medical need for effective alternative non-opioid analgesics.

An alternate pain modulatory system of great interest is the oxytocin (OT) neuronal network. Extensive research to date has shown that OT modulates pain. Importantly, OT has been shown to inhibit nociceptive pathways in peripheral nerve terminals, in the spinal cord, and in diverse brain pain regulatory systems including the periaqueductal grey, the amygdala, and the anterior cingulate cortex. This pattern is similar to the opioid system, thus explaining the efficacy of OT in modulating pain. Interestingly, modulation of oxytocin receptor (“OXTR”) using an OXTR agonist does not induce the side effects typical of opioid agonists. Opioid receptors and OXTR are neuropeptide receptors, thus given their activities, it is believed that OT can also be used to treat opioid addiction. Furthermore, based on its activity it is believed that OXTR agonists can also be used as non-opioid analgesics. Unfortunately, however, due to the instability of the native disulfide linkage, OT is unsuitable for use as a drug. Moreover, OT cannot readily cross the blood-brain barrier (BBB), so it is generally not well suited for use as a pharmaceutical. Recently, intranasal delivery of native OT has been reported. However, this intranasal delivery method misses important sites of OT action in the spinal cord and periphery. While small molecule OXTR ligands have been developed, they have yet to advance to the clinic.

Applications:
· Non-opioid pain relief
· Opioid Use Disorder (OUD)
· Substance Use Disorder (SUD)
· Autism spectrum disorders
· Asperger's Syndrome

Advantages:
· Derived from endogenous peptide
· Selective to oxytocin receptors
· Increased effectiveness in crossing the blood-brain barrier
· Increased stability in vivo 
· Potential for inhalation administration

Novel Peptides Bioavailable to the Brain for Non-Opioid Pain Relief and/or Addiction Treatment

ANG-(1-7) Derivative Oligopeptides and Methods for Using and Producing the Same

Glycolipid and Mixed Micelle Characterization via Diffusion-Ordered Spectroscopy

Glycopeptide and Classical Drug DesignThis invention relates to the glycosylation drug candidates to increase penetration, bioavailability, and stability.
 
Background: 
Transmembrane proteins provide a pathway for drugs to interact with a cell's interior. Drugs commonly target G-protein coupled receptors (GPCRs), comprising 40% of the market. Peptides and small molecule drugs directed toward GPCRs inside and outside of the central nervous system (CNS) can treat pain, Parkinson's disease, multiple sclerosis (MS), and other conditions. Carbohydrates improve drug bioavailability and stability to make treatment more effective for a given dose and remain effective during storage. Glycosylation allows for improved penetration of the blood-brain barrier (BBB) and access to the CNS. Glycosylated drugs are being developed for a variety of CNS conditions.
 
Applications:
· Treatment for conditions affecting the central nervous system
 
Advantages:
· Broadly targets GPCRs, involved in many biological processes
· Improved BBB penetration allows enhanced access to CNS and treatment of associated conditions
· Increased bioavailability reduces unnecessary dosage and increases application confidence
· Enhanced stability minimizes degradation due to transport, storage

KMap

Chemistry & Biochemistry - Science