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Computer-Aided Epitope Identification and Design of Epitope Mimetics
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
The approach is representative to the protein design philosophy implemented in the ROSETTA suite (David Baker’s group, refer to Bhardwaj et al. (2016)) – a de facto industry standard as of 2020 due to its academic origins and wide dissemination.
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
This chapter presented various protein engineering strategies in detail and their major contributions in engineering or redesigning the proteins for pharmaceutical and therapeutic research. As the global survey indicated that the pharmaceutical market in the next two decades will be replaced with protein/biomolecule-based therapeutics, these engineering strategies can be envisioned as foremost approaches to formulate next-generation therapeutics against several genetic, infectious, inflammatory, and autoimmune diseases. Although several protein formulations have been designed and approved in market, the design and generation of recombinant protein-based pharmaceuticals is in its infancy. This research area of protein design and engineering will further bloom with contemporary schemes of synthetic biology to produce protein therapeutics with outstanding clinical outcomes.
Vector Technology of Relevance to Nitrogen Fixation Research*
Published in Peter M. Gresshoff, Molecular Biology of Symbiotic Nitrogen Fixation, 2018
Reinhard Simon, Ursula B. Priefer
Jagadish et al.125 have discussed an extremely useful alternative, namely, how to use the mobilizable narrow host-range vectors of the pSUP series26,107 for introducing nonselectable modifications of cloned fragments, i.e., without adding an easily recognizable phenotypic trait, into a recipient genome. Such modifications include deletions, additions, or inversions of DNA fragments, and even alterations of single base pairs within the cloned DNA. The latter possibility is of special importance for site-specific mutagenesis of DNA signal sequences (e.g., in order to increase a particular promoter activity) or for the socalled protein design experiments which involve point mutations within a gene resulting in a defined amino acid exchange in the encoded polypeptide.
Protein drug delivery: current dosage form profile and formulation strategies
Published in Journal of Drug Targeting, 2020
Danilo Costa Geraldes, Viviane Lucia Beraldo-de-Araújo, Boris Odelion Pichihua Pardo, Adalberto Pessoa Junior, Marco Antônio Stephano, Laura de Oliveira-Nascimento
The mentioned issues may be solved by the design of proteins, production processes and dosage forms, as well as chemical modification/attachment. For protein design strategies, see [13] and future trends in Section “Drug delivery system trends on drug targeting”. Chemical modifications rely mainly on the covalent attachment of polyethylene glycol (PEG) for current commercial protein drugs, with around nine PEGylated protein medicines. The steric hindrance conferred by PEG reduces aggregation, protease digestion, immunogenicity and extends plasma half-life; stability in aqueous solution is also enhanced, allowing its storage in liquid form. On the other hand, chemical reactions for conjugation are time-consuming, costly and most protocols result in heterogeneous products, which are difficult to control [14,15]. Considering the PEG technology, extensive literature describes in detail the protocols, outcomes [15,16] and production solutions [17–19] for protein therapeutics. Other modifications will be briefly discussed in Section “Drug delivery system trends on drug targeting”.
Recent advances in automated protein design and its future challenges
Published in Expert Opinion on Drug Discovery, 2018
Dani Setiawan, Jeffrey Brender, Yang Zhang
The term protein design is, on many occasion, used interchangeably with the term protein engineering. Most protein engineering is achieved either through rational design, the evaluation of a few human selected mutations guided by comprehensive structural and biochemical knowledge, or by directed evolution by display technologies which evaluate very large mutant libraries generated by random mutagenesis at specific positions within the protein chains [11]. The success of this strategy is long and varied; nearly all protein therapeutics have been developed using some combination of the two strategies. The methods work in most cases because protein–protein interactions and enzymatic active sites are often relatively localized; evaluating one mutation site often only requires consideration of a few other sites in the immediate vicinity of the mutation – a mutation on one side of the protein surface usually does not impact the effect of a mutation on the other side. As long as the effect of the mutations is relatively localized, directed evolution by random mutagenesis can be an efficient way for searching for optimal protein sequences as a large area can be covered by independent screens.
An adapted consensus protein design strategy for identifying globally optimal biotherapeutics
Published in mAbs, 2022
Yanyun Liu, Kenny Tsang, Michelle Mays, Gale Hansen, Jeffrey Chiecko, Maureen Crames, Yangjie Wei, Weijie Zhou, Chase Fredrick, James Hu, Dongmei Liu, Douglas Gebhard, Zhong-Fu Huang, Akshita Datar, Anthony Kronkaitis, Kristina Gueneva-Boucheva, Daniel Seeliger, Fei Han, Saurabh Sen, Srinath Kasturirangan, Justin M. Scheer, Andrew E. Nixon, Tadas Panavas, Michael S. Marlow, Sandeep Kumar
In recent decades, several approaches have been developed to engineer proteins with more desirable functional and physicochemical attributes. These approaches span a broad range, from directed evolution31 to library designs and mutational analyses as part of protein structure activity (ProSAR) to de novo protein design17 and computational structure-based protein design.9,16,32,33 Consensus Protein Design takes advantage of evolutionarily conserved sequence motifs across different enzyme families to engineer enzymes with enhanced features, such as increased thermostability.12–14 In this study, we asked if an adapted Consensus Protein Design could be beneficial toward antibody engineering, even though the number of sequences available to construct the consensus molecules may be much smaller. An scFv was used as a model for this work because of previously reported developability issues related to this format.8,11,34 The eight anti-CD3 antibody sequences extracted from published patents (PUBs) appear to have been derived from a common murine SP34 antibody and possess highly similar light and heavy chain amino acid sequences. A set of 21 consensus molecules (CONs) were derived from all site-specific substitutions found throughout the scFv, 17 positions in total. These substitutions were found to retain similar levels of in vitro antigen binding and T cell-mediated tumor cytotoxicity (Supplementary Material). We then evaluated the properties of the CONs and PUBs using several computational and experimental techniques in a manner analogous to antibody lead candidate selection process. The data were subsequently analyzed with one-hot encoding and Ridge regression to determine the positions and the residues at those positions that make the greatest contributions toward desirable developability attributes. Combining these substitutions into one sequence, we were able to generate an optimized CombiCon molecule (CON24) with subtle but clear improvements in key attributes, namely, Tm, Tagg and aHIC RT in comparison with the single-point CON variants (Figure 3).