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The Macrophage Inflammatory Protein Family
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
A major limitation of the potential clinical utility of MIP-1α is its tendency to form large, heterogeneous, multimeric complexes.6,25,26,55 A principal consequence of this behavior is that clinical administration of the protein as a heterogeneous preparation could lead to varying efficacy, impaired tissue penetration and enhanced immunogenicity. An additional shortcoming is that during production and formulation, aggregation will result in heterogeneous pharmaceutical preparations. For clinical administration, therefore, a homogeneous preparation of defined molecular mass is preferable if not a regulatory requirement. This raises the immediate questions as to what is the optimal, active quaternary structure and what is the best way to achieve homogeneity.
Biochemistry Of The Murine Ia Antigens
Published in Soldano Ferrone, Chella S. David, Ia Antigens, 2019
There are a number of fascinating questions remaining to be answered about the biochemistry of the Ia Antigens. Basically, our knowledge of their primary structure is still at a rather primative stage and absolutely nothing is known about their secondary or tertiary structure. Likewise, relatively little is known for certain about the quaternary structure. For example, to what extent can combinatorial association of the various α and β chains occur? Can all Aα and Aβ chains or all Eα and Eβ chains combine to produce functional molecules? Can nonhomologous chains associate, i.e., do AαEβ and EαAβ molecules form and, if so, are they functionally relevant?
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Proteins, string of amino acids, play life-sustaining functions. They act as molecular transporters, sensors, signaling molecules, maintain cell shape, aid cell movement, and actively participate in the synthesis of other biomolecules (Goodsell, 1991). The secret to perform such diverse variety of functions by the protein is hidden in their amino acid sequence. Such a sequence of amino acids in turn encodes for the unique structural architecture of the protein. The three-dimensional or quaternary structure of the protein provides unique binding pockets, charged surfaces or catalytic sites that confer the unique functionality to the protein. Any alteration in the structure of the protein can either modulate or completely disrupt its functions (Voet and Voet, 2011). This implies that nature has bestowed on us the proficiency to play with the amino acid sequences and assemble them in a way that they perform a desired function. With this idea of rewiring proteins, a novel research area known as “protein engineering” has flourished.
A review of biosimilar in regulations and potential impact: Hong Kong perspectives
Published in Journal of Medical Economics, 2019
Vivian WY Lee, Franco WT Cheng
From the analytical perspective, a biosimilar should have (i) identical amino acid sequence (or primary structure); (ii) indistinguishable folding in both secondary, tertiary, and quaternary structure; (iii) glycosylation and related substances; and (iv) identical biological assays such as receptor binding, Complement-Dependent Cytotoxicity (CDC) assays, and NK cell Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) assays, to the originator1,4. However, despite strict controls, slight variations were still possible during post-translational modifications and could have a significant impact on effector function and immunogenicity. For example, the afucosylated Fc fragments of the FcγRIIIa could lead to a 100-fold higher affinity than the fucosylated version5. As a result, biosimilarity has to be confirmed both pre-clinically and clinically within a strict regulatory pathway.
Icosahedral boron clusters as modifying entities for biomolecules
Published in Expert Opinion on Biological Therapy, 2018
Tomasz M. Goszczyński, Krzysztof Fink, Janusz Boratyński
Conjugates of lysozyme with three distinct boron clusters (dodecaborate anion, nido-carborane and metallacarborane) have been synthesized using the thermal, solid state approach [63,64]. The attachment of a boron cluster had no significant influence on the secondary and tertiary structure of the protein. However, this slight modification strongly affects its quaternary structure, due to enhanced intermolecular interactions, which leads to an increased tendency to aggregation. All conjugates had a decreased thermal aggregation point (TAP), which is the temperature at which aggregation occurs. Conjugates with metallacarborane had a higher hydrodynamic diameter and a tendency for time-dependent aggregation, which suggests that metallacarboranes can cause spontaneous self-assembly of proteins [64]. The enzymatic activity of conjugates to hydrolyze bacterial cell walls was decreased in comparison to unmodified lysozyme, but aggregates of lysozyme-metallacarborane conjugates expressed twice the biological activity as that for non-aggregated conjugates.
Two novel variants of uncertain significance in GP9 associated with Bernard–Soulier syndrome: Are they true mutations?
Published in Platelets, 2018
P. Boisseau, C. Debord, M. Eveillard, A. Quéméner, M. Sigaud, M. Giraud, P. Talarmain, C. Thomas, G. Landeau, S. Bezieau, B. Pan Petesch, M. C. Béné, M. Fouassier
The variants identified in this patient involve two amino acids highly conserved in 12 different species, from zebrafish to human [6]. The first, p.Leu77Gln, is located in the Leucine-Rich Repeat (LRR) domain of the protein. The second, p.Asn85Lys, involves a region at the boundary between the LRR and its C-terminal region. Moreover, each of these variants is likely to induce physicochemical modifications of the protein, when comparing wild type and substituted forms. Leucine is a highly hydrophobic aminoacid, while the substituted glutamine, in p.Leu77Gln, is hydrophilic (Grantham’s distance 113 [0-215]). Similarly, the second variant induces a switch from the neutral asparagine to the cationic lysine (Grantham distance 94 [0-215]). Such drastic physicochemical changes would be expected to modify deeply the protein’s quaternary structure within the GP Ib-IX-V complex. Moreover, based on the 3D structure of a GPIbβ/GPIX ectodomain chimera [7], the two residues Leu77 and Asn85 appear completely buried (Figure 2) and therefore certainly contribute to the folding stability of GPIX. Their substitution with hydrophilic or charged amino acids is likely to affect not only the structure of the protein but also interactions with its partners in the formation of the GP Ib-IX-V complex.