Identification of amino acid residues critical for the B cell growth-promoting activity of HIV-1 matrix protein p17 variants

He, Wangxiao; Mazzuca, Pietro; Yuan, Weirong; Varney, Kristen M.; Bugatti, Antonella; Cagnotto, Alfredo; Giagulli, Cinzia; Rusnati, Marco; Marsico, Stefania; Diomede, Luisa; Salmona, Mario; Caruso, Arnaldo; Lu, Wuyuan; Caccuri, Francesca

doi:10.1016/j.bbagen.2018.09.016

Cited by 26 publications

(41 citation statements)

References 48 publications

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“…CRAC motifs are found in many viral proteins, and their role in cholesteroldependent virus-cell interactions have been demonstrated. For example, CRAC motifs are present in the HIV matrix protein р17, which was shown to participate in virus entry through the raft domains of the cell membranes [27,101]. The α-helical domain of the hepatitis C virus nonstructural protein NS5A, which is anchored at the cytoplasmic leaflet of the endoplasmic reticulum and is involved in replication hepatitis C virus, also contains CRAC motif [102].…”

Section: Cholesterol Recognition/interaction Amino Acid Consensus (Crmentioning

confidence: 99%

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Dunina-Barkovskaya¹

2021

Management of Dyslipidemia

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Some interactions of enveloped viruses with the host cell membrane have a cholesterol-dependent component, which may account for clinical manifestations of the infectious disease and can be used for the development of antiviral drugs. These cholesterol-dependent interactions can be mediated by cholesterol-recognition amino-acid consensus (CRAC) motifs present in viral proteins. The S protein of the SARS-CoV and SARS-CoV2 coronaviruses contains CRAC motifs that can be involved in the process of virus entry into the cell. Besides, during viral envelope formation, CRAC motifs can be responsible for binding of cell membrane cholesterol, leading to depletion of cell membrane cholesterol and subsequent malfunctioning of cellular cholesterol-dependent proteins, destabilization and permeabilization of cell membranes and, ultimately, to the death of infected cells. Understanding the mechanisms of cholesterol-dependent virus–cell interactions and the role of CRAC-containing viral proteins in the pathogenesis of the disease can serve as the basis for the development of new drugs that prevent both coronavirus entry into the cell and the damage of the infected cell during the viral morphogenesis. The target for such drugs can be the S-protein/cholesterol interface. CRAC-containing peptides derived from viral proteins may be among these agents. These peptides can also be used as experimental tools to study cholesterol-dependent virus–cell interactions.

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Section: Cholesterol Recognition/interaction Amino Acid Consensus (Crmentioning

confidence: 99%

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Dunina-Barkovskaya¹

2021

Management of Dyslipidemia

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“…All peptides were synthesized on rink amino MBHA resins by Fmoc chemistry as our previous reports [46][47][48]. After synthesis, peptides were cleaved by a reagent cocktail, which is consist of TFA (88%), phenol (5%), H2O (5%) and TIPS (2%).…”

Section: Experimental Section 41 Synthesis Of Peptides (Pmi-cys and Ingr)mentioning

confidence: 99%

A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties

Yan

Wang

et al. 2019

Biomaterials

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Nanostructures formed with bioactive peptides offer an exciting prospect in clinical oncology as a novel class of therapeutic agents for human cancers. Despite their therapeutic potential, however, peptide-based nanomedicines are often inefficacious in vivo due to low cargo-loading efficiency, poor tumor cell-targeting specificity and limited drug accumulation in tumor tissues. Here, we describe the design, via assembly of a p53-activating peptide termed PMI, functionalized PEG and fluorescent lanthanide oxyfluoride nanocrystals, of a novel nanotheranostic shaped in flexible rods. This lanthanide-peptide nanorod or LProd of bionic nature exhibited significantly enhanced tumor-targeting and -imaging properties compared to its spherical counterpart. Importantly, LProd potently inhibited tumor growth in a mouse model of human colon cancer through activating tumor suppressor protein p53 via MDM2/MDMX antagonism, while maintaining a highly favorable biosafety profile. Our data demonstrate that LProd as a multifunctional theranostic platform is ideally suited for tumor-specific peptide drug delivery with real-time disease tracking, thereby broadly impacting clinical development of antitumor peptides.

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“…CD spectra of variants at a concentration of 20 μmol/L in 10 mmol/L phosphate buffer (pH 7.4) were obtained at room temperature on a J-810 spectropolorimeter (Jasco, Easton, MD) using a 1-mm quartz cuvette as previous reports [25][26][27] . Scanned area was from 250 nm to 190 nm, and the scanning speed was 50 nm/min.…”

Section: Spectroscopymentioning

confidence: 99%

“…The Fluorescence polarization-based competitive binding assays were performed in Microfluor® 2, 96-well black plates (Thermo Fisher Scientific) and readings were taken using a Tecan Infinite M2000 fluorescence plate reader. Serially diluted Lupbin or corresponding peptide were prepared in Tris-HCl buffered saline (10 mmol/L Tris, 150 mmol/L NaCl, 1 mmol/L EDTA, pH 7.0) and incubated with 200 nmol/L [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] p53-FITC/ MDM2 or 50 nmol/L [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] p53-FITC/MDMX in a total volume of 150 μL per well. After 2 h incubation at room temperature, fluorescence polarization was measured at λex = 470 nm and λem = 530 nm.…”

Section: Fluorescence Polarization-based Competitive Binding Assaymentioning

confidence: 99%

“…*Stand for that the molecular weight was measured by ESI-MASS; C: circular dichroism spectra of PMI, SP0, SP1, SP2 and SP3. The experiment was repeated independently for 3 times with similar results concentrations of stapled PMI were applied to pre-incubated MDM2/ [18][19][20][21][22][23][24][25][26] p53-FITC or MDMX/ [18][19][20][21][22][23][24][25][26] p53-FITC complexes, respectively, [ Figure 3B and C] and the IC50 and Kd values are tabulated in Figure 3D. Compared with the N-acetylated and C-amidated wild-type peptide PMI, SP1 and SP2 were bound more strongly to MDM2 and MDMX.…”

Section: Dimethylbromobenzene-cysteine Stapled Peptide Specifically Tmentioning

confidence: 99%

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A dimethylbromobenzene-cysteine stapled peptide dual inhibitor of the p53-MDM2/MDMX interactions

Jiang¹,

Jin²,

Liu³

et al. 2019

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Aim: Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, thereby playing a critical role in protecting cells from malignant transformation. The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival. Methods: In this work, we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas. Moreover, we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at (i, i+4) positions, and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX, termed p53-MDM2/MDMX inhibitor (PMI). Results: Notably, all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinity as PMI. More importantly, this stapling functionally rescued PMI that, on its own, failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation. Conclusion: Taken together, this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy, but promises an important new tool for peptide drug discovery and development for a variety of human diseases.

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Identification of amino acid residues critical for the B cell growth-promoting activity of HIV-1 matrix protein p17 variants

Cited by 26 publications

References 48 publications

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

Cholesterol Recognition Motifs (CRAC) in the S Protein of Coronavirus: A Possible Target for Antiviral Therapy?

A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties

A dimethylbromobenzene-cysteine stapled peptide dual inhibitor of the p53-MDM2/MDMX interactions

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