Utilizing Combinatorial Chemistry and Rational Design: Peptidic Tweezers with Nanomolar Affinity to DNA Can Be Transformed into Efficient Vectors for Gene Delivery by Addition of a Lipophilic Tail

2013 ◽  
Vol 52 (52) ◽  
pp. 14016-14020 ◽  
Author(s):  
Hannes Y. Kuchelmeister ◽  
Sarah Karczewski ◽  
Aljona Gutschmidt ◽  
Shirley Knauer ◽  
Carsten Schmuck
Keyword(s):  
Gene Delivery ◽  
Combinatorial Chemistry ◽  
Rational Design

Utilizing Combinatorial Chemistry and Rational Design: Peptidic Tweezers with Nanomolar Affinity to DNA Can Be Transformed into Efficient Vectors for Gene Delivery by Addition of a Lipophilic Tail

2013 ◽  
Vol 125 (52) ◽  
pp. 14266-14270 ◽  
Author(s):  
Hannes Y. Kuchelmeister ◽  
Sarah Karczewski ◽  
Aljona Gutschmidt ◽  
Shirley Knauer ◽  
Carsten Schmuck
Keyword(s):  
Gene Delivery ◽  
Combinatorial Chemistry ◽  
Rational Design

Structurally Mapping Antigenic Epitopes of Adeno-Associated Virus 9: Development of Antibody Escape Variants

2021 ◽  
Author(s):  
Shanan N. Emmanuel ◽  
J. Kennon Smith ◽  
Jane Hsi ◽  
Yu-Shan Tseng ◽  
Matias Kaplan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Monoclonal Antibodies ◽  
Gene Delivery ◽  
General Population ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Transduction Efficiency ◽  
Viral Neutralization ◽  
Patient Cohort ◽  
Antigenic Epitopes

Adeno-associated viruses (AAV) serve as vectors for therapeutic gene delivery. AAV9 vectors have been FDA approved, as Zolgensma®, for the treatment of spinal muscular atrophy and is being evaluated in clinical trials for the treatment of neurotropic and musculotropic diseases. A major hurdle for AAV-mediated gene delivery is the presence of pre-existing neutralizing antibodies in 40 to 80% of the general population. These pre-existing antibodies can reduce therapeutic efficacy through viral neutralization, and the size of the patient cohort eligible for treatment. In this study, cryo-electron microscopy and image reconstruction was used to define the epitopes of five anti-AAV9 monoclonal antibodies (MAbs); ADK9, HL2368, HL2370, HL2372, and HL2374, on the capsid surface. Three of these, ADK9, HL2370, and HL2374, bound on or near the icosahedral 3-fold axes, HL2368 to the 2/5-fold wall, and HL2372 to the region surrounding the 5-fold axes. Pseudo-atomic modeling enabled the mapping and identification of antibody contact amino acids on the capsid, including S454 and P659. These epitopes overlap with previously defined parvovirus antigenic sites. Capsid amino acids critical for the interactions were confirmed by mutagenesis followed by biochemical assays testing recombinant AAV9 (rAAV9) variants capable of escaping recognition and neutralization by the parental MAbs. These variants retained parental tropism and had similar or improved transduction efficiency compared to AAV9. These engineered rAAV9 variants could expand the patient cohort eligible for AAV9-mediated gene delivery by avoiding pre-existing circulating neutralizing antibodies. IMPORTANCE The use of recombinant AAVs (rAAVs) as delivery vectors for therapeutic genes is becoming increasingly popular, especially following the FDA approval of Luxturna® and Zolgensma®, based on serotypes AAV2 and AAV9, respectively. However, high titer anti-AAV neutralizing antibodies in the general population, exempts patients from treatment. The goal of this study is to circumvent this issue by creating AAV variant vectors not recognized by pre-existing neutralizing antibodies. The mapping of the antigenic epitopes of five different monoclonal antibodies (MAbs) on AAV9, to recapitulate a polyclonal response, enabled the rational design of escape variants with minimal disruption to cell tropism and gene expression. This study, which included four newly developed and now commercially available MAbs, provides a platform for the engineering of rAAV9 vectors that can be used to deliver genes to patients with pre-exiting AAV antibodies.

Rational design of cationic cyclooligosaccharides as efficient gene delivery systems

2008 ◽  
pp. 2001 ◽  
Author(s):  
Alejandro Díaz-Moscoso ◽  
Patricia Balbuena ◽  
Marta Gómez-García ◽  
Carmen Ortiz Mellet ◽  
Juan M. Benito ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Rational Design ◽  
Delivery Systems ◽  
Efficient Gene

scholarly journals A Kinetic Model of Oligonucleotide–Brush Interactions for the Rational Design of Gene Delivery Vectors

2019 ◽  
Vol 20 (6) ◽  
pp. 2218-2229 ◽  
Author(s):  
Fengjin Qu ◽  
Danyang Li ◽  
Xiaoyan Ma ◽  
Fang Chen ◽  
Julien E. Gautrot
Keyword(s):  
Gene Delivery ◽  
Kinetic Model ◽  
Rational Design ◽  
Gene Delivery Vectors

scholarly journals The Effects of Combinatorial Chemistry and Technologies on Drug Discovery and Biotechnology – a Mini Review

2014 ◽  
Vol 13 (2) ◽  
pp. 87-108 ◽  
Author(s):  
Pierfausto Seneci ◽  
Giorgio Fassina ◽  
Vladimir Frecer ◽  
Stanislav Miertus
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Expert Opinion ◽  
High Throughput ◽  
Combinatorial Chemistry ◽  
Rational Design ◽  
Combinatorial Libraries ◽  
Computer Assisted ◽  
Future Trends ◽  
The Impact

Abstract The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of “combinatorial thinking” in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided.

Polyamines and novel polyamine conjugates interact with DNA in ways that can be exploited in non-viral gene therapy

2003 ◽  
Vol 31 (2) ◽  
pp. 397-406 ◽  
Author(s):  
I.S. Blagbrough ◽  
A.J. Geall ◽  
A.P. Neal
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Rational Design ◽  
Molecular Probes ◽  
Dna Condensation ◽  
Viral Gene ◽  
Viral Gene Therapy ◽  
Lipid Moiety ◽  
Polyamine Conjugates ◽  
Fluorescent Molecular Probes

As a part of our continuing studies on ‘Polyamines and their role in human disease’ we are investigating how polyamines, and especially how novel polyamine conjugates, interact with DNA. We are studying how these conjugates interact with circular plasmids in order to produce nanometre-sized particles suitable for transfecting cells. Our considerations of structure--activity relationships (SAR) within naturally occurring and synthetic polyamines have shown the significance of the inter-atomic distances between the basic nitrogen atoms. As these atoms are typically fully protonated under physiological conditions, they exist in equilibrium as polyammonium ions. The covalent addition of a lipid moiety, typically one or two alkyl or alkenyl chains, or a steroid, allows much greater efficiency in DNA condensation and in the cellular transfection achieved. Thus efficient DNA condensation and subsequently drug delivery (i.e. with DNA as the drug) can be brought about using novel polyamine conjugates. Taking further advantage of the functionalization of specific steroids (e.g. cholesterol and certain bile acids), we have designed and prepared novel fluorescent molecular probes as tools to throw light on the problematic steps in non-viral gene delivery which still impede efficient gene therapy. Thus, the current aims of our research are to understand, design and prepare small-molecule lipopolyamines for non-viral gene therapy (NVGT). The rational design and practical preparation of non-symmetrical polyamine carbamates and amides, based on steroid templates of cholesterol and the bile acid lithocholic acid as the lipid moiety, provides fluorescent molecular probes that condense DNA. These novel lipopolyamine conjugates mimic the positive charge distribution found in the triamine spermidine and the tetra-amine spermine alkaloids. After optimizing their SAR, these fluorescent probes will be useful in monitoring gene delivery in NVGT.

scholarly journals Rational design and characterisation of a linear cell penetrating peptide for non-viral gene delivery

2020 ◽  
Author(s):  
Emma M. McErlean ◽  
Monika Ziminska ◽  
Cian M. McCrudden ◽  
John W. McBride ◽  
Stephen P. Loughran ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Rational Design ◽  
Viral Gene ◽  
Cell Penetrating Peptide ◽  
Cell Penetrating ◽  
Viral Gene Delivery ◽  
Linear Cell
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