Bioinformatics and Biosimulations as Toolbox for Peptides and Peptidomimetics Design: Where Are We?

D’Annessa, Ilda; Leva, Francesco Saverio Di; Teana, Anna La; Novellino, Ettore; Limongelli, Vittorio; Marino, Daniele Di

doi:10.3389/fmolb.2020.00066

Cited by 46 publications

(51 citation statements)

References 129 publications

(142 reference statements)

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“…The identification of the unbinding path of GC7, together with the comparative description of the structural and dynamical differences between aDHS and hDHS, provides a broad set of crucial information for the design of a new class of inhibitors, not only able to block the hypusination process but also the formation of the DHS–eIF5A complex. In the first instance, these information can be used to filter out the most promising potential inhibitory compounds during a virtual screening routine and, second, to drive the design of peptides/peptidomimetics, molecules highly suitable to inhibit protein–protein interactions (D'Annessa et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase in Sulfolobus solfataricus: A Thermophilic Model for the Design of New Hypusination Inhibitors

et al. 2020

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Translation factor 5A (eIF5A) is one of the most conserved proteins involved in protein synthesis. It plays a key role during the elongation of polypeptide chains, and its activity is critically dependent on hypusination, a post-translational modification of a specific lysine residue through two consecutive enzymatic steps carried out by deoxyhypusine synthase (DHS), with spermidine as substrate, and deoxyhypusine hydroxylase (DOHH). It is well-established that eIF5A is overexpressed in several cancer types, and it is involved in various diseases such as HIV-1 infection, malaria, and diabetes; therefore, the development of inhibitors targeting both steps of the hypusination process is considered a promising and challenging therapeutic strategy. One of the most efficient inhibitors of the hypusination process is the spermidine analog N1-guanyl-1,7-diaminoheptane (GC7). GC7 interacts in a specific binding pocket of the DHS completely blocking its activity; however, its therapeutic use is limited by poor selectivity and restricted bioavailability. Here we have performed a comparative study between human DHS (hDHS) and archaeal DHS from crenarchaeon Sulfolobus solfataricus (aDHS) to understand the structural and dynamical features of the GC7 inhibition. The advanced metadynamics (MetaD) classical molecular dynamics simulations show that the GC7 interaction is less stable in the thermophilic enzyme compared to hDHS that could underlie a lower inhibitory capacity of the hypusination process in Sulfolobus solfataricus. To confirm this hypothesis, we have tested GC7 activity on S. solfataricus by measuring cellular growth, and results have shown the lack of inhibition of aIF5A hypusination in contrast to the established effect on eukaryotic cellular growth. These results provide, for the first time, detailed molecular insights into the binding mechanism of GC7 to aDHS generating the basis for the design of new and more specific DHS inhibitors.

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Section: Discussionmentioning

confidence: 99%

Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase in Sulfolobus solfataricus: A Thermophilic Model for the Design of New Hypusination Inhibitors

et al. 2020

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“…Both the NMR and ESR data show a direct interaction of C8 with the membrane bilayers composed with a higher concentration of the zwitterionic DOPC phospholipids. In order to provide mechanistic insight into the peptide/membrane binding interaction, we performed atomistic molecular dynamics simulations, a well-established approach to study peptides functional and structural properties (D'Annessa et al, 2020 ), on C8 in six different membrane models composed by the same ratios of zwitterionic/negatively charged lipids used in the experiments. Specifically, they are (i) pure DOPC 100:0, (ii) DOPC/DOPG 90:10, (iii) 60:40, (iv) 40:60, (v) 10:90, and (vi) pure DOPG 0:100 ( Figures 4 , 5 ).…”

Section: Resultsmentioning

confidence: 99%

Binding of the Anti-FIV Peptide C8 to Differently Charged Membrane Models: From First Docking to Membrane Tubulation

et al. 2020

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“…Therefore, these components also provide a direction for researchers to develop new diagnostic antigens for brucellosis, and the development of immunoinformatic technology provides tools for the development of new diagnostic antigens. Immunoinformatic is based on bioinformatic tools, an emerging science that integrates life sciences, computer science, and mathematics [19,20]. Immunoinformatic technology uses bioinformatic tools to treat pathogens without cultivating them.…”

Section: Discussionmentioning

confidence: 99%

Paper-based ELISA Diagnosis Technology for Human Brucellosis Based on a Multiepitope Fusion Protein

Yin

Bai

et al. 2021

Preprint

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Background: At present, as a serious zoonotic infectious disease, the incidence of brucellosis is increasing each year worldwide, exhibiting signs of resurgence. Brucellosis seriously threatens the health of humans, and it is necessary to strengthen the methods utilized for its rapid and accurate diagnosis.Methods: Bioinformatic technology was used to predict B-cell epitopes of the main outer membrane proteins of Brucella and subsequently verified the antigenicity of these epitopes. Prepared a Brucella multiepitope fusion protein and verified the antigenicity of the protein by indirect ELISA. Whatman filter paper was then modified with nano-zinc oxide to construct a paper-based ELISA (p-ELISA) technology for the diagnosis of brucellosis.Results: A total of 22 linear B cell epitopes were predicted. Each epitope could recognize some brucellosis sera. The constructed multiepitope fusion protein had good antigenicity and significantly reduced cross-reaction compared with LPS. The sensitivity and specificity of the method were 92.38% and 98.35%, the positive predictive value was 98.26%, and the negative predictive value was 91.67%.Conclusions: A multiepitope fusion protein of Brucella was successfully prepared, and a rapid diagnostic technique for brucellosis was established. This technology has potential application value and can be used for the rapid diagnosis of brucellosis.

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Bioinformatics and Biosimulations as Toolbox for Peptides and Peptidomimetics Design: Where Are We?

Cited by 46 publications

References 129 publications

Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase in Sulfolobus solfataricus: A Thermophilic Model for the Design of New Hypusination Inhibitors

Insights Into the Binding Mechanism of GC7 to Deoxyhypusine Synthase in Sulfolobus solfataricus: A Thermophilic Model for the Design of New Hypusination Inhibitors

Binding of the Anti-FIV Peptide C8 to Differently Charged Membrane Models: From First Docking to Membrane Tubulation

Paper-based ELISA Diagnosis Technology for Human Brucellosis Based on a Multiepitope Fusion Protein

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