scholarly journals Affinity maturation of the RLIP76 Ral binding domain to inform the design of stapled peptides targeting the Ral GTPases

2020 ◽  
pp. jbc.RA120.015735
Author(s):  
Catherine A Hurd ◽  
Paul Brear ◽  
Jefferson Revell ◽  
Sarah Ross ◽  
Helen R Mott ◽  
...  
Keyword(s):  
Rational Design ◽  
First Generation ◽  
Second Generation ◽  
Affinity Maturation ◽  
Peptide Inhibitors ◽  
Binding Domain ◽  
Stapled Peptides ◽  
Stapled Peptide ◽  
Protein Protein Interaction ◽  
Ral Gtpases

Ral GTPases have been implicated as critical drivers of cell growth and metastasis in numerous Ras-driven cancers. We have previously reported stapled peptides, based on the Ral effector RLIP76, that can disrupt Ral signaling. Stapled peptides are short peptides that are locked into their bioactive form using a synthetic brace. Here, using an affinity maturation of the RLIP76 Ral-binding domain, we identified several sequence substitutions that together improve binding to Ral proteins by more than 20-fold. Hits from the selection were rigorously analyzed to determine the contributions of individual residues and two 1.5 Å co-crystal structures of the tightest-binding mutants in complex with RalB revealed key interactions. Insights gained from this maturation were used to design second-generation stapled peptides based on RLIP76 that exhibited vastly improved selectivity for Ral GTPases when compared to the first-generation lead peptide. The binding of second-generation peptides to Ral proteins was quantified and the binding site of the lead peptide on RalB was determined by NMR. Stapled peptides successfully competed with multiple Ral-effector interactions in cellular lysates.  Our findings demonstrate how manipulation of a native binding partner can assist in the rational design of stapled peptide inhibitors targeting a protein–protein interaction.

scholarly journals Entropy of Stapled Peptide Inhibitors in Free State is the Major Contributor to the Improvement of Binding Affinity

2021 ◽  
Author(s):  
Ilona Christy Unarta ◽  
Jianchao Xu ◽  
Yuan Shang ◽  
Carina Hey Pui Cheung ◽  
Ruichi Zhu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Small Molecule ◽  
Protein Interaction ◽  
Small Molecule Inhibitors ◽  
Peptide Inhibitors ◽  
Major Contributor ◽  
Protein Targets ◽  
Stapled Peptide ◽  
Protein Protein Interaction ◽  
Energetic Interactions

Stapled peptides are promising protein-protein interaction (PPI) inhibitors that can increase binding potency. Different from small-molecule inhibitors in which binding mainly depends on energetic interactions with their protein targets, stapled...

scholarly journals Computational Design of Stapled Peptide Inhibitor against SARS-CoV-2 Receptor Binding Domain

2021 ◽  
Author(s):  
Asha Rani Choudhury ◽  
Atanu Maity ◽  
Sayantani Chakraborty ◽  
Rajarshi Chakrabarti
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Computational Design ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Conformational Restriction ◽  
Stapled Peptides ◽  
Stapled Peptide ◽  
Free Peptide ◽  
The One

Since its first detection in 2019, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been the cause of millions of deaths worldwide. Despite the development and administration of different vaccines, the situation is still worrisome as the virus is constantly mutating to produce newer variants some of which are highly infectious. This raises an urgent requirement to understand the infection mechanism and thereby design therapeutic-based treatment for COVID-19. The gateway of the virus to the host cell is mediated by the binding of the Receptor Binding Domain (RBD) of the virus spike protein to the Angiotensin-Converting Enzyme 2 (ACE2) of the human cell. Therefore, the RBD of SARS-CoV-2 can be used as a target to design therapeutics. The α1 helix of ACE2 which forms direct contact with the RBD surface has been used as a template in the current study to design stapled peptide therapeutics. Using computer simulation, the mechanism and thermodynamics of the binding of six stapled peptides with RBD have been estimated. Among these, the one with two lactam stapling agents has shown binding affinity, sufficient to overcome RBD-ACE2 binding. Analyses of the mechanistic detail reveal that a reorganization of amino acids at the RBD-ACE2 interface produces favorable enthalpy of binding whereas conformational restriction of the free peptide reduces the loss in entropy to result in higher binding affinity. The understanding of the relation of the nature of the stapling agent with their binding affinity opens up the avenue to explore stapled peptides as therapeutic against SARS-CoV-2.

scholarly journals Impact of HIV-1 Integrase L74F and V75I Mutations in a Clinical Isolate on Resistance to Second-Generation Integrase Strand Transfer Inhibitors

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Atsuko Hachiya ◽  
Karen A. Kirby ◽  
Yoko Ido ◽  
Urara Shigemi ◽  
Masakazu Matsuda ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Virological Failure ◽  
Rational Design ◽  
Clinical Case ◽  
First Generation ◽  
Second Generation ◽  
Strand Transfer ◽  
Integrase Strand Transfer Inhibitors ◽  
Mutation Pattern ◽  
Hiv 1

ABSTRACT A novel HIV-1 integrase mutation pattern, L74F V75I, which conferred resistance to first-generation integrase strand transfer inhibitors (INSTIs), was identified in a clinical case with virological failure under a raltegravir-based regimen. Addition of L74F V75I to N155H or G140S Q148H increased resistance levels to the second-generation INSTIs dolutegravir (>385- and 100-fold, respectively) and cabotegravir (153- and 197-fold, respectively). These findings are important for the development of an accurate system for interpretation of INSTI resistance and the rational design of next-generation INSTIs.

Do remittances differ depending on migration pathway and length of stay?

2016 ◽  
Vol 1 (1) ◽  
pp. 105-118
Author(s):  
Anita Pugliese ◽  
Julie Ray ◽  
Neli Esipova
Keyword(s):  
Length Of Stay ◽  
First Generation ◽  
Second Generation ◽  
Global Analysis ◽  
Large Sample ◽  
Migration Pathway ◽  
First Generation Migrants ◽  
Second Generation Migrants

This paper reports the results from Gallup’s global analysis of the likelihood of first-generation migrants, second-generation migrants and the native-born to send financial help in the form of money or goods to others inside or outside their respective country of residence. The findings in this paper are based on more than 450,000 interviews conducted through Gallup’s World Poll in 157 countries in 2012, 2013 and 2014. The sample includes more than 26,000 first-generation migrants and more than 20,000 second-generation migrants. The large sample enables Gallup to analyze first-generation migrants by the duration of their stay in their adopted country and compare their remittance behaviors with second-generation migrants and the native-born.

Marcuse and Habermas's Political Ideas in English

2019 ◽  
pp. 215
Author(s):  
Asaad Abdullwahab AbdulKarim ◽  
Waleed Massaher Hamad ◽  
Salah Ibrahim Hamadi
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Frankfurt School ◽  
Western Thought ◽  
Political Ideas ◽  
Important Impact

Abstract     The Frankfurt School is characterized by its critical nature and it is the result of the Marxist socialist thought as it contributed to the development of the German thought in particular and the Western thought in general through important ideas put forward by a number of pioneers in the various generations of the school and most notably through the leading pioneer in the first generation, Marcuse, and the leading pioneer of the second  generation, Habermas, whose political ideas had an important impact on global thinking and later became the basis of the attic of many critical ideas. In spite of the belief of the school members in the idea of the criticism of power and community, each had his own ideas that distinguish him from the others.

Pharmakotherapie update

2020 ◽  
Vol 25 (1) ◽  
pp. 23-32
Author(s):  
Gerd Laux
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Therapeutische Maßnahmen ◽  
Second Generation Antipsychotics

Für die Therapie schizophrener Erkrankungen sind seit fast 60 Jahren Antipsychotika/Neuroleptika aufgrund ihrer antipsychotischen Wirkung von zentraler Bedeutung. Die Einteilung kann unter verschiedenen Gesichtspunkten erfolgen (chemische Struktur, neuroleptische Potenz, Rezeptorprofil), heute werden üblicherweise unterschieden typische (traditionelle, klassische, konventionelle) Antipsychotika der ersten Generation ‒ »First Generation Antipsychotics« (FGA) ‒ und sog. atypische (»neuere«) Neuroleptika bzw. Antipsychotika der zweiten Generation ‒»Second Generation Antipsychotics« (SGA). Hierzu zählen Aripiprazol, Asenapin, Cariprazin, Clozapin, Olanzapin, Quetiapin, Risperidon, Sertindol und Ziprasidon. Hierbei handelt es sich um keine homogene Gruppe – sowohl neuropharmakologisch (Wirkmechanismus), als auch hinsichtlich klinischem Wirkprofil und dem Nebenwirkungsspektrum bestehen z. T. erhebliche Unterschiede. Neben der Akut-Medikation ist eine Langzeitmedikation bzw. Rezidivprophylaxe mit Antipsychotika für die Rehabilitation vieler schizophrener Patienten im Sinne eines »Stresspuffers« von grundlegender Bedeutung. In Placebo-kontrollierten Studien trat bei Patienten, die über ein Jahr behandelt wurden, bei etwa 30% unter Neuroleptika ein Rezidiv auf, unter Placebo bei mehr als 70%. Für die Langzeitbehandlung bietet sich der Einsatz von Depot-Neuroleptika an, neu entwickelt wurden Langzeit-Depot-Injektionen mit Intervallen von bis zu 3 Monaten. Grundsätzlich ist die niedrigstmögliche (wirksame) Dosis zu verwenden. Im Zentrum der Nebenwirkungen (UAW) standen lange Zeit extrapyramidal-motorische Bewegungsstörungen (EPMS), mit der Einführung von Clozapin und anderen atypischen Antipsychotika der zweiten Generation gewannen andere Nebenwirkungen an Bedeutung. Hierzu zählen Gewichtszunahme, Störungen metabolischer Parameter und ein erhöhtes Risiko für Mortalität und zerebrovaskuläre Ereignisse bei älteren Patienten mit Demenz. Entsprechende Kontrolluntersuchungen sind erforderlich, für Clozapin gibt es aufgrund seines Agranulozytose-Risikos Sonderbestimmungen. Immer sollte ein Gesamtbehandlungsplan orientiert an der neuen S3-Praxisleitlinie Schizophrenie der DGPPN aufgestellt werden, der psychologische und milieu-/sozial-therapeutische Maßnahmen einschließt. Standard ist heute auch eine sog. Psychoedukation, für Psychopharmaka liegen bewährte Patienten-Ratgeber vor.

The Inheritors’ Coming of Age

2018 ◽  
Author(s):  
Elisabeth Schimpfössl
Keyword(s):  
First Generation ◽  
Second Generation ◽  
Coming Of Age ◽  
Next Generation ◽  
Privileged Status ◽  
The Rich

Chapter 7 focuses on the upbringing of the second generation of the Russian bourgeoisie. As the first generation of wealthy Russians grows older, they are becoming more aware of their own mortality and are preparing to hand over their wealth to the next generation. It seems that rich Russians are yet to find a convincing narrative to justify their children’s legitimate entitlement to wealth that does not contradict their own everyday ideology of being self-made. Nevertheless, a two-pronged approach is emerging. First, in line with the shift toward new modesty, children are being encouraged to cultivate a habitus of privilege, as Sherman suggests in the case with wealthy US Americans, which makes them appear morally worthy in an environment marked by extreme inequality. Second, via their philanthropy the rich are supporting institutions and scholars in an effort to strengthen a dynamic capitalist environment in which privileged status is respected.

Sign in / Sign up

Export Citation Format

Share Document