SB-PEPTIDE offers MiniAp-4 peptide. MiniAp-4 peptide is a short nontoxic derivative of apamin (a neurotoxin from bee venom) used as a blood-brain barrier (BBB) shuttle peptide.
The blood brain barrier has been known as the major barrier for drug delivery to the brain. Therefore,BBB shuttle peptides can be used to bind therapeutic molecules to allow their distribution in the central nervous system (CNS).
BBB shuttle peptides are a good way to enable central nervous system therapies because these molecules are more economical,less immunogenic,and have higher chemical versatility than large proteins. On the other hand,they are often metabolized by serum proteases.To overcome this problem,some peptides found in venoms can target the CNS directly,such as apamin,which has been modified to form MiniAp-4 (a non-toxic and non-immunogenic apamin derivative) which stands out as the vector of choice. Indeed,this carrier,MiniAp-4 peptide,is protease-resistant and has negligible toxicity and immunogenicity.
Data from Oller-Salvia B et al. MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery. Angew Chem Int Ed Engl. 2016.
Technical specification
Sequence : Dap-KAPETALD-NH2
Cyclization : Dap1-D9
MW : 911.47 g/mol (C39H65N11O14)
Purity : > 95%
Available customization : Biotinylation,azide/alkyne functionalization,drug conjugation…
Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively,their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin,a neurotoxin from bee venom,was minimized by reducing its complexity,toxicity,and immunogenicity,while preserving brain targeting,active transport,and protease resistance. Among the analogues designed,the monocyclic lactam-bridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore,MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.
Venoms have recently emerged as a promising field in drug discovery due to their good selectivity and affinity for a wide range of biological targets. Among their multiple potential applications,venoms are a rich source of blood-brain barrier (BBB) peptide shuttles. We previously described a short nontoxic derivative of apamin,MiniAp-4,which can transport a wide range of cargoes across the BBB. Here,we have studied the conformation of the proline residue of a range of MiniAp-4 analogues by high-field NMR techniques,with the aim to identify whether there is a direct relation between the cis/trans population and a range of features,such as the capacity to transport molecules across a human-based cellular model and stability in various media. The most promising candidate showed improved transport properties for a relevant small fluorophore.
2- Sánchez-Navarro M,Teixidó M,Giralt E. Acc Chem Res. 2017
The cell membrane,the gastrointestinal tract,and the blood-brain barrier (BBB) are good examples of biological barriers that define and protect cells and organs. They impose different levels of restriction,but they also share common features. For instance,they all display a high lipophilic character. For this reason,hydrophilic compounds,like peptides,proteins,or nucleic acids have long been considered as unable to bypass them. However,the discovery of cell-penetrating peptides (CPPs) opened a vast field of research. Nowadays,CPPs,homing peptides,and blood-brain barrier peptide shuttles (BBB-shuttles) are good examples of peptides able to target and to cross various biological barriers. CPPs are a group of peptides able to interact with the plasma membrane and enter the cell. They display some common characteristics like positively charged residues,mainly arginines,and amphipathicity. In this field,our group has been focused on the development of proline rich CPPs and in the analysis of the importance of secondary amphipathicity in the internalization process. Proline has a privileged structure being the only amino acid with a secondary amine and a cyclic side chain. These features constrain its structure and hamper the formation of H-bonds. Taking advantage of this privileged structure,three different families of proline-rich peptides have been developed,namely,a proline-rich dendrimer,the sweet arrow peptide (SAP),and a group of foldamers based on γ-peptides. The structure and the mechanism of internalization of all of them has been evaluated and analyzed. BBB-shuttles are peptides able to cross the BBB and to carry with them compounds that cannot reach the brain parenchyma unaided. These peptides take advantage of the natural transport mechanisms present at the BBB,which are divided in active and passive transport mechanisms. On the one hand,we have developed BBB-shuttles that cross the BBB by a passive transport mechanism,like diketoperazines (DKPs),(N-MePhe)n,or (PhPro)n. On the other hand,we have investigated BBB-shuttles that utilize active transport mechanisms such as SGV,THRre,or MiniAp-4. For the development of both groups,we have explored several approaches,such as the use of peptide libraries,both chemical and phage display,or hit-to-lead optimization processes. In this Account,we describe,in chronologic order,our contribution to the development of peptides able to overcome various biological barriers and our efforts to understand the mechanisms that they display. In addition,the potential use of both CPPs and BBB-shuttles to improve the transport of promising therapeutic compounds is described.
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