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Low pH-induced Insertion Peptide

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  • Xinyi Huang

As we all know, the cell membrane is a biological membrane that can separate the cell interior from the outside environment. The cell membrane is alternatively permeable and able to control what enters and exits the cell, thereby promoting the transport of molecules needed for survival. The cell membrane works as a selective filter and can only allow certain molecules to get inside or go outside the cell. In the process of exploring the drug’s efficacy, the scientists have inevitably encountered some embarrassing situation. For example, some molecules do work in the cell, but these molecules were hindered by cell membranes, and they cannot get into cell by ordinary transportation.

To solve this problem, scientists have tried a lot of methods. For instance, taking advantage of some viruses which have the ability of infecting cell, then cross the cell membrane to delivery DNA or RNA into cell. We can also use transfection to do the same thing. But these methods have identical withdraw, they cannot infect with high specificity and more or less are toxic to cells. Since these tradition methods cannot meet our requirements, scientists try their best to find better methods.

In the process of finding new method, the cell membrane’s structure makes us be in a dilemma. The center of the lipid bilayer contains almost no water and excludes molecules likesugarsor salts that dissolve in water. However the peptides and proteins containing these extremely hydrophobic sequences can hardly solve in water. You can’t have your cake and eat it. So the biosynthesis of integral membrane proteins can weather insert spontaneously into a lipid bilayer or not becomes a big problem.

Fortunately in 1997, Hunt et al. have observed the spontaneous, pH-dependent insertion of water-soluble peptide to form α helix across lipid bilayer. In 2006, Yana K et al. use a low pH-induced insertion peptide to transport cargo molecules across the cell membranes of living cells by attaching the cargo to its C terminus. At neutral pH, the peptide–cargo conjugate interacts weakly with a cell membrane. Then at low pH, the peptide spontaneously forms a transmembrane helix and its C terminus inserted in the cytoplasm. And make use of reducing the disulfide bond releases the cargo.

The amazing peptides are a family of above 36 amino acid peptides. The peptide does not exhibit any secondary helical structure in solution or on the plasma membrane at physiological pH; however, when it inserts into a lipid bilayer, it forms a transmembrane helix and delivers molecules into cells. Many studies show that various types of cargo molecules can attached by disulfides and can be released via reduction in the cytoplasm. The cargo molecules include peptide nucleic acids, cyclic peptides, and organic compounds. Since a high extracellular acidity is typical of many pathological conditions (such as infarcts, atherosclerotic lesions, stroke-afflicted tissue, tumors, damaged tissue resulting from trauma, or sites of inflammation or infection) or creating artificially, low pH-induced insertion peptide may be a useful tool for alternative delivery of cargos for drug therapy, diagnostic imaging, or cell regulation.

In fact, this low pH-induced insertion peptide has been found long ago, it seems not a big deal. But when it connect with antimiRs(antisense oligomers), things going to be changed. MicroRNAs are short non-codingRNAs, they expressed in different tissues and cell types that inhibit the expression of target genes. In the same way, microRNAs are key components in numerous biological processes, and disturbanced microRNA expression is associated with many human diseases. Some certain microRNA plays a causal role in the form and maintenance of cancer when they overexpressed. The inhibition of microRNAs using antimiRs is a developing therapeutic strategy. Whereas, the in vivo efficacy of recent antimiR technologies is set up by physical and cellular barriers to delivery into target cells, and this technology is short of specificity.

Now we have got several pieces of puzzle: the most tumour microenvironments are acidic, antimiRs can rescue the cancers caused by overexpressing microRNA and a low pH-induced insertion peptide. So we can use low pH-induced insertion peptide -antimiR target to the tumour microenvironment Christopher J. Cheng introduced a novel antimiR delivery method that targets the acidic tumour microenvironment, escapes from systemic clearance by the liver, and promotes cell entry by a non-endocytic pathway. They find that the combination of antimiRs to a low pH-induced insertion peptide produces a new construct that could target the tumour microenvironment, tranlocate antimiRs across cell membranes under acidic conditions. This study introduces a novel model for utilizing antimiRs as anti-cancer drugs can have great impacts on the field of targeted drugs delivery. The confocal images are A549 cells cultured with labeled low pH-induced insertion peptide-antimiR at different pH. There is seldom labeled low pH-induced insertion peptide -antimiR delivery to the cells at pH 7.4. However there is plenty of labeled low pH-induced insertion peptide -antimiR delivered into cytoplasm at pH 6.2.

The process of cancer spread is always the disturbing problem in cancer treatment. Surprisingly the low pH-induced insertion peptide -antimiR can target to metastasized tumours. Importantly, when treat healthy wild type mice with high dose of low pH-induced insertion peptide-antimiR, there is no significant damage of organ function. In addition, the white blood cell levels, organ mass and body mass were all under normal condition.

The low pH-induced insertion peptide-antimiR is a good method to treat tumours, but the size and polarity of cargo molecules that low pH-induced insertion peptide can translocate through the cell membrane remain to be studied. So there is still a long way to go. But on the positive side, utilization of low pH-induced insertion peptide to target acidic tumour microenvironment is a widely acceptable method for microRNA silencing. We can also use this low pH-induced insertion peptide to treat other diseases, such as inevitable metabolic acidosis trend caused by hypoxia ischemia, then the use of this low pH-induced insertion peptide may also be able to deliver some drugs to treat the injury created by the hypoxia or inflammation. We can also use such tools as a means of orientated therapy of acidosis, and may provide a special method to solve metabolic disorders happened in some special cells. All in all, I think the low pH-induced insertion peptide is a very useful tool in clinic treatment.

References

[1] Yana K et al. Translocation of molecules into cells by pH-dependent insertion of a transmembrane helix. (2006) PANS

[2] John C. Deacon et al. Targeting acidity in diseased tissues: Mechanism and applications of the membrane-inserting peptide, pHLIP. (2014) Archives of Biochemistry and Biophysics

[3] Wikipedia


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