scholarly journals A guide to maximizing the therapeutic potential of protein–polymer conjugates by rational design

2018 ◽  
Vol 47 (24) ◽  
pp. 8998-9014 ◽  
Author(s):  
Jeong Hoon Ko ◽  
Heather D. Maynard
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Careful Planning ◽  
Therapeutic Applications ◽  
Polymer Conjugates ◽  
Protein Polymer ◽  
Conjugation Chemistry ◽  
Polymer Conjugation ◽  
Selection Of

Careful planning in the selection of the protein, polymer, conjugation chemistry, and analysis can help maximize the potential of protein–polymer conjugates for therapeutic applications.

Anticoagulant Activity of Hirulog™, a Direct Thrombin Inhibitor, in Humans

1993 ◽  
Vol 69 (02) ◽  
pp. 157-163 ◽  
Author(s):  
Irving Fox ◽  
Adrian Dawson ◽  
Peter Loynds ◽  
Jane Eisner ◽  
Kathleen Findlen ◽  
...  
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
Direct Thrombin Inhibitor ◽  
Controlled Study ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Thrombotic Disease ◽  
Dose Dependent

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

On the immunological properties of penicillins

1971 ◽  
Vol 179 (1057) ◽  
pp. 411-432 ◽  
Keyword(s):  
Proteolytic Enzyme ◽  
Continuous Process ◽  
Polymeric Materials ◽  
Small Peptides ◽  
Physiological Conditions ◽  
Polymer Conjugates ◽  
Protein Polymer ◽  
Penicillanic Acid ◽  
Insoluble Form ◽  
Polyvalent Antigens

Penicilloylated proteins which may be found as impurities in 6-amino-penicillanic acid can be exhaustively digested by pronase to yield amino acids and small peptides. This degradation converts the potent polyvalent antigens into a mixture of mostly monovalent haptens which are much less immunogenic and less capable of eliciting immune reactions in sensitized animals. In order to avoid the contamination of 6-aminopenicillanic acid with a proteolytic enzyme, pronase was converted into a water insoluble form by coupling it with bromoacetyl cellulose. This insoluble derivative of pronase retains its activity and broad specificity. It can be readily removed from the medium upon completion of the impurity degradation, to be used repeatedly in a continuous process. The immunological manifestations associated with penicillins are not completely abolished by removal or degradation of protein impurities. Another important cause for these manifestations appears to be polymeric materials which are formed in penicillins. Such polymeric materials were isolated from ampicillin and shown to be capable of binding spontaneously to proteins (e.g. bovine serum albumin). The protein-polymer conjugates, which are formed under physiological conditions (pH 7.4, 37 °C), were found to be immunogenic and to provoke the formation of polymer-specific antibodies.

scholarly journals Crosslinking of Self-Assembled Protein–Polymer Conjugates with Divanillin

2020 ◽  
Author(s):  
Zihao Li ◽  
Yanyan Jiang ◽  
Kilian Wüst ◽  
Manuela Callari ◽  
Martina H. Stenzel
Keyword(s):  
Polymer Conjugates ◽  
Protein Polymer ◽  
Self Assembled

Click inspired synthesis of hexa and octadecavalent peripheral galactosylated glycodendrimers and their possible therapeutic applications

2019 ◽  
Vol 43 (31) ◽  
pp. 12475-12482 ◽  
Author(s):  
Anand K. Agrahari ◽  
Anoop S. Singh ◽  
Ashish Kumar Singh ◽  
Nidhi Mishra ◽  
Mala Singh ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Therapeutic Applications

Click inspired glycodendrimers comprising a rigid hexapropargyloxy benzene core with peripheral β-d-galactopyranosidic units were developed and evaluated for their therapeutic potential.

Automation Tool Preparation in the Conditions of Production

2015 ◽  
Vol 770 ◽  
pp. 739-743 ◽  
Author(s):  
A.S. Yuanyushkin ◽  
D.V. Lobanov ◽  
D.A. Rychkov
Keyword(s):  
Comparative Analysis ◽  
Rational Design ◽  
Economic Effect ◽  
Optimal Choice ◽  
Processing Efficiency ◽  
Time Required ◽  
The Given ◽  
High Processing ◽  
Selection Of

The key task of the tool manufacturing is to create or to choose such a type of tool, which would permit to provide high processing efficiency, the best tool`s workability and the quality of the machined surfaces with minimum expenses and resources. The optimal choice of the constructive tool modifications from a variety of options takes much time required for the preparation of the tool to work. To solve this problem, we have developed software that allows you to create, organize and carry out a comparative analysis of structural instruments in order to identify rational option for the given conditions of production. Ordering and selection of a rational design of the instrument is carried out in accordance with established procedures of modeling and comparative analysis of design solutions. Application software can reduce design time technological process by 80...90%, and get a substantial annual economic effect.

scholarly journals Therapeutic potential of polypeptide-based conjugates: Rational design and analytical tools that can boost clinical translation

2020 ◽  
Vol 160 ◽  
pp. 136-169 ◽  
Author(s):  
Tetiana Melnyk ◽  
Snežana Đorđević ◽  
Inmaculada Conejos-Sánchez ◽  
María J. Vicent
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Clinical Translation ◽  
Analytical Tools
Sign in / Sign up

Export Citation Format

Share Document