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Purine nucleoside phosphorylase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Accumulated PRPP in turn drives the de novo pathway of purine synthesis. In one patient, physicochemical evidence of structural gene mutation was found in an increased Km for inosine and decreased heat stability [12]. Because no activity at all could be detected in the propositus, these studies were carried out in heterozygotes in which the six electrophoretically separate bands seen in normals were present. The normal human enzyme has a trimeric structure [21]. It has been postulated [3] that in the patient there is a catalytically inactive trimer.
Recombinant and modified vaccines and adjuvants used for allergen immunotherapy
Published in Richard F. Lockey, Dennis K. Ledford, Allergens and Allergen Immunotherapy, 2020
Jeffrey Stokes, Thomas B. Casale
In a clinical trial, patients received only one preseasonal treatment course but developed robust IgG1, IgG2, and IgG4 antibody responses against natural Bet v 1, Bet v 1–related allergens, allergens from alder (Aln g1) and hazel (Cor a 1), and cross-reactive food allergens, such as apple, carrot, and celery. One treatment course was enough to suppress the seasonal pollen exposure-induced increase in allergen-specific IgE in both active treatment groups versus the placebo group. Patients treated with the trimer showed a decrease in Bet v 1–specific TH2 responses, thought to be secondary to the high-treatment Bet v 1 trimer dose, and a greater allergen-specific TH1 response than that produced by the recombinant wild-type allergen [5,6].
Disease Prediction and Drug Development
Published in Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam, Introduction to Computational Health Informatics, 2019
Arvind Kumar Bansal, Javed Iqbal Khan, S. Kaisar Alam
The third technique is BLAST (Basic Local Alignment Search Tool). The technique starts with matching smaller trimers (three characters long subsequences), and then extends the match using similarity-score matching matrix such as BLOSUM-62 so the matching-score remains above a threshold-value. For DNA matching, nucleotide-matrix is used (matching nucleotide score = +5, and a mismatch score of −4 or −3). Further extension of a segment is suspended if the matching score drops below a threshold-value. This process is repeated for every trimer unless it merges with another extended subsequence. The scheme is fast and is used in finding homologs – similar sequences. After identifying the higher matching segments, the probability of the two sequences being aligned is computed using probability theory. If the probability meets the user-specified probability, then two sequences are considered similar. Example 10.6 illustrates it. Besides these popular techniques, there are other techniques such as FASTA- and HMM-based matching.
Mechanistic PK/PD modeling to address early-stage biotherapeutic dosing feasibility questions
Published in mAbs, 2023
Joshuaine Grant, Fei Hua, Joshua F. Apgar, John M. Burke, Diana H. Marcantonio
In this retrospective analysis, the T-cell engager model for solid tumors in Applied BioMath Assess™ was once again parameterized from literature and simulated to predict toxic and effective doses and therapeutic index.13–15,27,33,40–43 This model mechanistically describes the binding and crosslinking of TAA and CD3 to form an active trimolecular complex or “trimer”, which is used as the surrogate for activity (Figure 3A). The model was simulated to predict solitomab PK and trimer formation. The toxic dose was projected as the dose required to achieve a time-averaged 500 trimers per T cell in the gastrointestinal compartment, while the effective dose was projected as the dose required to achieve the same 500 trimers per T cell in the tumor compartment. The threshold of 500 trimers was chosen based on experimental data suggesting 200 to 1000 receptors per cell is the minimum antigen density required for CAR-T or T-cell engager activity.44,45 Model simulations predicted a toxic dose of 28 µg per day, comparable to the observed maximum tolerated dose of 24 µg per day. The model predicted an effective dose of 13.5 µg per day, within 2-fold of the toxic dose, suggesting a minimal therapeutic index (Figure 3B). This conclusion was robust across a range of drug affinities and half-lives. If applied prospectively, this analysis could have identified the development risks associated with this target.
Targeting the N332-supersite of the HIV-1 envelope for vaccine design
Published in Expert Opinion on Therapeutic Targets, 2020
Thandeka Moyo, Dale Kitchin, Penny L. Moore
A sequential immunization strategy may provide a more focused pathway to bNAbs through vaccination. HIV-1 sequential vaccination encompasses the use of a priming immunogen that engages B cells with bNAb precursor receptors, which will ideally expand upon subsequent immunization boosts with modified immunogens to mature into bNAbs. As bNAb precursors generally do not bind to unmodified Env gp140 trimers, various germline-targeting immunogens have been developed [93,94]. However, there are currently a limited number of published germline-targeting and boosting immunogens aimed specifically at activating N332-supersite-specific B cells. Steichen et al (2016) developed a modified BG505 SOSIP trimer which lacked key N133 and N137 glycans in the V1 region as well as a combination of mutations in the V1 and V3 regions to expose the PGT121-precusor epitope. The resultant trimer, 11MUTB, was able to activate PGT121-like antibody responses in knock-in mice – mice in which the majority of B cells express the antibody of interest, and which thus provide a highly sensitive measure of immune responses. Escolano et al (2016) performed a similar study using mice expressing the precursor of PGT121, priming with a similar BG505-derived modified germline targeting immunogen. Subsequent boosts, informed by ELISA measurements of serum affinity, included less mutated forms of the trimer, with the final boosts consisting of a combination of native-like trimers. This important proof-of-principle study showed that this strategy was able to induce heterologous Tier 2 neutralizing responses [95].
Current strategies to enhance the targeting of polydopamine-based platforms for cancer therapeutics
Published in Journal of Drug Targeting, 2020
Yin Xiao, Lin Chen, Xiaoliang Chen, Bin Xiao
Some scholars suggested that the backbone of PDA was based on the non-covalent interactions between aromatic rings of the dopamine monomer (such as charge transfer, π–π stacking or hydrogen bonding), similar to other synthetic pathways for bio-supramolecular polymers [25]. However, Lee's and Hong's group put forward another argument that the synthesis pathway of PDA was based on a combination of covalent polymerisation and non-covalent self-assembly exhibiting a competing relationship. On the one hand, the dimer was formed by DHI through an oxidative polymerisation way, and subsequently further reacts with another dopamine molecule to form a trimer (DHI–DA–DHI) [26]. On the other hand, a trimer (DA–DHI–DA) could also be formed by two dopamine molecules and one DHI molecule through diverse non-covalent bonds [27,28]. Interestingly, in the initial synthesis stage, the covalent bonds played a key role, and then the influence of non-covalent bonds was gradually higher than the covalent bonds [26,29]. The synthesis of PDA was finally completed by the combination of the two methods mentioned above. The detailed synthesis process is described in Figure 1.