scholarly journals De Novo Design of Immunoglobulin-like Domains

2021 ◽  
Author(s):  
Tamuka M Chidyausiku ◽  
Soraia R Mendes ◽  
Jason C Klima ◽  
Ulrich Eckhard ◽  
Scott Houliston ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Design ◽  
Beta Sheets ◽  
Central Feature ◽  
X Ray Crystallography ◽  
New Class ◽  
Non Local ◽  
Beta Structure ◽  
Antibody Derivatives ◽  
Current Engineering

Antibodies and antibody derivatives such as nanobodies contain immunoglobulin-like (Ig) [beta]-sandwich scaffolds which anchor the hypervariable antigen-binding loops and constitute the largest growing class of drugs. Current engineering strategies for this class of compounds rely on naturally existing Ig frameworks, which can be hard to modify and have limitations in manufacturability, designability and range of action. Here we develop design rules for the central feature of the Ig fold architecture - the non-local cross-[beta]; structure connecting the two [beta]-sheets - and use these to de novo design highly stable seven-stranded Ig domains, confirm their structures through X-ray crystallography, and show they can correctly scaffold functional loops. Our approach opens the door to the design of a new class of antibody-like scaffolds with tailored structures and superior biophysical properties.

scholarly journals A defined structural unit enables de novo design of small-molecule–binding proteins

Science ◽  
2020 ◽  
Vol 369 (6508) ◽  
pp. 1227-1233 ◽  
Author(s):  
Nicholas F. Polizzi ◽  
William F. DeGrado
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Small Molecules ◽  
Structural Unit ◽  
De Novo ◽  
Computational Design ◽  
De Novo Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Groups

The de novo design of proteins that bind highly functionalized small molecules represents a great challenge. To enable computational design of binders, we developed a unit of protein structure—a van der Mer (vdM)—that maps the backbone of each amino acid to statistically preferred positions of interacting chemical groups. Using vdMs, we designed six de novo proteins to bind the drug apixaban; two bound with low and submicromolar affinity. X-ray crystallography and mutagenesis confirmed a structure with a precisely designed cavity that forms favorable interactions in the drug–protein complex. vdMs may enable design of functional proteins for applications in sensing, medicine, and catalysis.

De Novo Design, Synthesis, and In Vitro Evaluation of a New Class of Nonpeptidic Inhibitors of the Malarial Enzyme Plasmepsin II

ChemBioChem ◽  
2002 ◽  
Vol 3 (11) ◽  
pp. 1137-1141 ◽  
Author(s):  
David A. Carcache ◽  
Simone R. Hörtner ◽  
Andreas Bertogg ◽  
Christoph Binkert ◽  
Daniel Bur ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Design ◽  
Design Synthesis ◽  
In Vitro Evaluation ◽  
New Class ◽  
Plasmepsin Ii

scholarly journals Role of backbone strain in de novo design of complex α/β protein structures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nobuyasu Koga ◽  
Rie Koga ◽  
Gaohua Liu ◽  
Javier Castellanos ◽  
Gaetano T. Montelione ◽  
...  
Keyword(s):  
De Novo ◽  
Protein Structures ◽  
De Novo Design ◽  
Structure Packing ◽  
Nmr Structures ◽  
Β Protein ◽  
Wide Range ◽  
Explicit Consideration ◽  
Non Local

AbstractWe previously elucidated principles for designing ideal proteins with completely consistent local and non-local interactions which have enabled the design of a wide range of new αβ-proteins with four or fewer β-strands. The principles relate local backbone structures to supersecondary-structure packing arrangements of α-helices and β-strands. Here, we test the generality of the principles by employing them to design larger proteins with five- and six- stranded β-sheets flanked by α-helices. The initial designs were monomeric in solution with high thermal stability, and the nuclear magnetic resonance (NMR) structure of one was close to the design model, but for two others the order of strands in the β-sheet was swapped. Investigation into the origins of this strand swapping suggested that the global structures of the design models were more strained than the NMR structures. We incorporated explicit consideration of global backbone strain into the design methodology, and succeeded in designing proteins with the intended unswapped strand arrangements. These results illustrate the value of experimental structure determination in guiding improvement of de novo design, and the importance of consistency between local, supersecondary, and global tertiary interactions in determining protein topology. The augmented set of principles should inform the design of larger functional proteins.

scholarly journals De novo design of a non-local β-sheet protein with high stability and accuracy

2018 ◽  
Vol 25 (11) ◽  
pp. 1028-1034 ◽  
Author(s):  
Enrique Marcos ◽  
Tamuka M. Chidyausiku ◽  
Andrew C. McShan ◽  
Thomas Evangelidis ◽  
Santrupti Nerli ◽  
...  
Keyword(s):  
High Stability ◽  
De Novo ◽  
De Novo Design ◽  
Non Local ◽  
Stability And Accuracy ◽  
Β Sheet

scholarly journals De Novo design and synthesis of dipyridopurinone derivatives as visible-light photocatalysts in productive guanylation reactions

2021 ◽  
Author(s):  
Yameng Wan ◽  
Hao Wu ◽  
Nana Ma ◽  
Jie Zhao ◽  
Zhiguo Zhang ◽  
...  
Keyword(s):  
Visible Light ◽  
De Novo ◽  
De Novo Design ◽  
Design And Synthesis ◽  
New Class

Described here is the de novo design and synthesis of a series of 6H-dipyrido[1,2-e:2',1'-i]purin-6-ones (DPs) as a new class of visible-light photoredox catalysts (PCs). The synthesized DP1-5 showed their λAbs(max)...

A Plug-and-Play Approach for the De Novo Generation of Dually Functionalised Bispecifics

2019 ◽  
Author(s):  
Antoine Maruani ◽  
Peter A. Szijj ◽  
Calise Bahou ◽  
João C. F. Nogueira ◽  
Stephen Caddick ◽  
...  
Keyword(s):  
De Novo ◽  
Therapeutic Index ◽  
Antibody Fragments ◽  
Bispecific Antibodies ◽  
Full Potential ◽  
Mechanisms Of Resistance ◽  
Large Excess ◽  
Chemical Methods ◽  
New Class ◽  
Novel Approach

<p>Diseases are multifactorial, with redundancies and synergies between various pathways. However, most of the antibody-based therapeutics in clinical trials and on the market interact with only one target thus limiting their efficacy. The targeting of multiple epitopes could improve the therapeutic index of treatment and counteract mechanisms of resistance. To this effect, a new class of therapeutics emerged: bispecific antibodies.</p><p>Bispecific formation using chemical methods is rare and low yielding and/or requires a large excess of one of the two proteins to avoid homodimerisation. In order for chemically prepared bispecifics to deliver their full potential, high-yielding, modular and reliable cross-linking technologies are required. Herein, we describe a novel approach not only for the rapid and high-yielding chemical generation of bispecific antibodies from native antibody fragments, but also for the site-specific dual functionalisation of the resulting bioconjugates. Based on orthogonal clickable functional groups, this strategy enables the assembly of functionalised bispecifics with controlled loading in a modular and convergent manner.</p>

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