Multitarget Peptides

Wednesday, April 23, 2014

Sponsored by Senn Chemicals

Introduction

For many years the pharma industry has focused on drugs that selectively interact with high affinity for a single therapeutic target, because side effects were associated with off-target interactions. It has however become clear that several drugs derive their successful therapeutic action from the interaction with multiple targets. Addressing multiple targets can result in safer drugs with less adverse reactions because the therapeutic effects of multiple mode of actions are often synergistic, whereas adverse effects are not. (1) In principle, patients can be treated with a cocktail of drugs in the form of two or more tablets, or by co-formulation of several active ingredients into a single tablet. However this may lead to complications arising from differences in pharmacokinetics and pharmacodynamics between patients, and to drug-drug interactions. Therefore, the strategy to design a single compound that is interacting with several therapeutic targets becomes attractive. Several methods have been developed to obtain such “designed multiple ligands” (DML’s); the most simple one being to link two pharmacophores through a linker of varying length.(2) Linking two pharmacophores in such a way results in “bi-functional” ligands (conjugates), that interact in a monovalent fashion with the two different targets. So called “bivalent” ligands that interact simultaneously with two targeted receptors, for example in a receptor heterodimer, require a long spacer (20 – 50 Å), (3) so several described bivalent ligand are most likely bifunctional ones.(4) When the two pharmacophores are linked directly or with a very short linker, so called “fused” DML’s are obtained. A challenge is to use overlapping pharmacophore features of both ligands to design “merged” DML’s.

Figure 1: Bifunctional ligends consisting of linked- fused- or merged pharmacophores (phar)

Several bi-functional non-peptidic drugs are already on the market or in clinical trials. (2) Peptides are pre-eminently suited for these approaches given their easy modular assembly and their often extended pharmacophores. An area that has attracted considerable interest is the development of peptide-based analgesic DMLs with a new activity profile.(4-7)

Case Study: Opioid/Non-opioid Hybrids for Analgesia

The treatment of severe pain, especially chronic and neuropatic pain is still a major challenge. Chronic opioid treatment results in serious side effects, such as nausea, vomiting, constipation and the development of tolerance. Analgesia, but also side effects are mostly associated with the µ opioid receptors. In contrast, morphine tolerance and dependence was strongly attenuated by the -antagonist Tyr-Tic(CH2-NH)Phe-Phe-NH2 (TIPP[]).(8) Therefore, bi-functional opioids targeting several opioid receptor subtypes attracted interest as potent analgesics with reduced side effects. For this purpose, several non-peptidic/non-peptidic,(7) non-peptidic/peptidic and peptidic/peptidic opioid DMLs were prepared.(4-6) Recent peptidic DML’s aiming at the µ- and -opioid subtype receptors include the merger of the superpotent Dmt-DALDA, which has a triple mode of action: µ-receptor activation, inhibition of norepinephrine uptake and release of endogenous opioid peptides, with the antagonist

TICP(). The resulting hybrid was shown to produce less tolerance, and was active after subcutaneous administration, indicating that it was able to cross the BBB (whereas TICP[ ] is not).(9) A compound with a similar µ-agonist/-antagonist profile was obtained by conjugating endomorphin-2 with Dmt-Tic. (10)

Figure 2: Bifunctional opioid peptides

Targeting opioid heterodimer complexes is however only one of the potential research avenues in the opioid control of pain. Over the years, the role of other receptors in pain modulation has been demonstrated.

Cholecystokinin (CCK) was shown to attenuate morphine-induced analgesia; it can be regarded as an antiopioid.(11) CCK2 receptor antagonists were shown to reverse tolerance and to attenuate the development of dependence. Hybrids with a partially overlapping opioid and CCK antagonist pharmacophore RSA 504 and RSA 601 were developed. The compounds had the expected high agonism for the µ- and -opioid receptors, and acted as antagonists at the CCK2 receptor. They showed potent activity in vivo in a model of neuropathic pain. Intrathecal administration of RSA 504 and RSA 601 did not result in antinociceptive tolerance, demonstrating that these multi-target DMLs offer a new approach for neuropathic pain, lacking the side effects of conventional opioids.(12)

Figure 3: Opioid-CCK hybrids

Neurotensin induces analgesia that is not mediated through the opioid system. An opioid-neurotensin hybrid PK20 showed potent µ- and -opioid agonism, a good affinity to the NTS1 receptor with moderate agonist potency. It induced long-lasting analgesia after intrathecal as well as intravenous administration, with a potency about 150 times that of morphine.(13)

Figure 4: PK20, an opioid-NT hybrid

It is known that neurokinin 1 receptor antagonists have a potential to act as analgesics independent of the opioid system. Additionally it was demonstrated that co-administration of a Substance P antagonist can enhance the analgesic action of the opioid peptide biphalin.(14) NK1 antagonists also have a beneficial effect on the occurrence of nausea and vomiting. The first multi-target chimera was reported by Lipkowski, based on a casomorphin fragment linked to a SP fragment.(15) It served as lead or AWL-60, which, despite moderate µ- and -opioid receptor affinities, showed a potent and prolonged in vivo analgesia after it administration.(16) In AA501, a more potent biphalin fragment was combined with the Cbz-Trp fragment which acts an a NK1 antagonist. The hybrid produced potent antinociception in inflammatory as well as in neuropatic pain models after it injection. Interestingly, the same group reported that a hybrid of an opioid agonist and a tachykinin agonist (AWL-3106) also produced effective analgesia without the development of tolerance, and was active after intravenous application.(16) Hruby et al. developed a set of hybrids with overlapping opioid and NK1 pharmacophores, and a C-terminal Trp-(3’,5’-bistrifluorometyl)benzyl ester or amide. The Tyr analogue TY027 showed high analgesic potency in acute and neuropatic pain models after central or intravenous administration.(17) The Dmt1 analogue showed improved bioactivity compared to TY027.(18)

Figure 5: Opioid-NK1 hybrids

A peptidomimetic approach was followed by Ballet et al.(19) A potent opioid tetrapeptide analog AN81 was developed, containing the conformationally constrained Aba (4-amino-tetrahydro-2-benzazepinone). A search for NK1 peptidomimetic anagonists identified the Ac-Aba-Gly-NMe-(3’,5’-bistrifluorometyl)benzyl containing mimetic as a potent antagonist. Overlapping the common pharmacophores resulted in a compact DML with potent agonism at the opioid µ- and δ-receptors and NK1 antagonism. The compound SBCHM01 produced strong analgesia in acute pain models after intravenous injection, indicating that it is able to cross the BBB. The in vivo potency of the hybrid is however somewhat lower than that of the isolated opioid component AN81. Unexpectedly the compound showed the appearance of tolerance after repeated administration.(20) A factor that can govern the overall bioactivity profile of the hybrids is the ratio of activities of the individual pharmacophores. Recent research efforts provided the new hybrid KGCHM2, which is a more potent opioid agonist and a weaker NK1 antagonist. Its in vivo evaluation in a neuropatic pain model after iv administration is ongoing.(21)

Figure 6:Merged opioid ago nist-NK1 a ntagonists

Conclusion

The paradigm shift from selective peptides to multi-target peptides has resulted in promising results in the field of the treatment of pain, and especially of neuropatic pain. Several other opioid/non-opioid hybrids are reported: opioid-melanocortin, (22) opioid-bradykinin,(23) opioid-cannabinoid (24) and opioid-chemokine receptor CCR5 ligands, (25) which result in compounds with completely new activity profiles. The misconception that peptides do not cross the BBB and have a short duration of action (26) has once again been disproved. It is not surprising that also in other domains, such obesity treatment using GLP-1/GIP hybrids (27) or peptide heterodimers targeting multiple receptors as radiochemicals for molecular imaging, (28) are developed. The flexibility of peptide assembly and the use of designed amino acids are key to this success.

References

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