- They prevent the occurrence and development of cancer in various ways.
- ——Development history——
- In 2020, Professor Jianfeng CAI of the University of South Florida published the article “rational design of right handed heterogeneous Peptidomics as inhibitors of protein protein protein interactions” on JMC [7], and designed completely unnatural peptides to inhibit the binding of MDM2 / mdmx and p53.
- There have been many studies on the design of polypeptide drugs to inhibit the interaction between MDM2 and p53.
They prevent the occurrence and development of cancer in various ways.
P53, an important cancer related protein, plays the role of “gene guard” in life activities. Normal p53 can maintain the stability of genome through DNA damage and repair.
For cancer cells, p53 will block the cell cycle and promote its apoptosis, so as to inhibit cancer cells. P53 is a disordered protein in structure.
The N-terminal is the transcriptional activation region, the middle part is the DNA binding region, and the C-terminal includes the tetramer domain and regulatory region.
MDM2, an important protein regulating the function of p53, is a ubiquitin ligase. MDM2 can inhibit the function of p53 by directly binding to the transcriptional activation region of p53 or ubiquitination. P53 regulates the transcription of MDM2, that is, there is a negative feedback regulatory pathway between MDM2 and p53. Mdmx is a homologous protein of MDM2.
The heterodimer formed by mdmx binding with MDM2 can enhance its ability to ubiquitinate p53. Therefore, drug molecules designed to inhibit the interaction between MDM2 and p53 can promote the activation of p53, so as to achieve the purpose of inhibiting cancer.
——Development history——
In 1996, Nikola P. pavletich published a paper [2] on science. The crystal structure of interaction between the N-terminal of p53 and MDM2 was analyzed.
The 15 amino acid residues at the N-terminal of p53 protein formed amphiphilic α helix. The hydrophobic side (mainly F19, w23 and L26) was bound to the hydrophobic crack of MDM2 through hydrophobic force and steric hindrance effect.
The analysis of this structure provides a structural basis for the design of peptide drugs and competitive inhibition of their interactions by imitating the interaction interface.
Moreover, compared with targeting p53, it is easier to design helical peptide mimicking p53 to target MDM2; the strategy of directly targeting p53 needs excellent researchers with more experience in drug design.
In 2007, Loren D. walensky published a paper on JACS [3]. By imitating the 15 amino acid residues at the N-terminal of p53, we designed peptide drugs, and inserted amino acids with R-group as olefins.
Through olefin metathesis strategy, the polypeptide was cyclized (called stapled peptide) to further enhance its α helix and improve its stability. The activity of sah-p53-8 was the best.
The binding activity of sah-p53-8 with MDM2 was 55 nm. In terms of cell activity, sah-p53-8 had 8 um inhibitory activity on sjsa-1 cells.
Subsequently, Loren D. walensky studied the mechanism of sah-p53-8 on cancer cell [4] in 2010, and analyzed the crystal structure of sah-p53-8 on MDM2 in May 2011. The “stapling chain” structure of sah-p53-8 peptide has hydrophobic interaction with MDM2.
In 2013, Tomi K. Sawyer published an article [6] in PNAS, which further improved the activity and designed a new stapling peptide atsp-7041, which targets the dual functions of MDM2 and mdmx.
Through screening and optimization, they found that the interaction between MDM2 and Gln at 17, ASN at 21, and CBA on Leu at 26 could enhance its interaction with MDM2; Arg at 24 could significantly improve its solubility;
and two alanine ala at position 29 and 30 were added for optimization. Finally, it further enhanced its ability to combine MDM2 and mdmx, which were 0.9nm and 6.8nm, respectively.
Atsp-7041 has submicromolar inhibitory activity on MCF-7 cells and sjsa-1 cells.
In 2020, Professor Jianfeng CAI of the University of South Florida published the article “rational design of right handed heterogeneous Peptidomics as inhibitors of protein protein protein interactions” on JMC [7], and designed completely unnatural peptides to inhibit the binding of MDM2 / mdmx and p53.
The polypeptide uses 1:1 α / sulfono – γ – AA as monomer, which is a kind of 413 helix of right hand, which can completely resist the degradation of enzyme and improve the bioavailability.
After the first round of screening, peptide 1 with good activity was obtained. The binding constants of MDM2 and mdmx were 19.3 nm and 66.8 nm, respectively.
Then, cross linking strategy was used to construct the amide bond lactam bridge for further optimization. The activity of polypeptide 14 (Fig. 8) was the best, IC50 = 4.9um. In contrast, the fluorescence of icu1 was 13.1 m before polarization.
——Summary——
There have been many studies on the design of polypeptide drugs to inhibit the interaction between MDM2 and p53.
There are many strategies worthy of our study, such as introducing unnatural amino acids to enhance the interaction between MDM2 and MDM2, improving the stability and helicity of polypeptides through ring closing strategy, enhancing the solubility and enhancing the resistance to enzymes.
These strategies may be applied to other drug design systems and give us inspiration and help.
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