Full Sequence Amino Acid Scanning of θ-Defensin RTD-1 Yields a Potent Anthrax Lethal Factor Protease Inhibitor

Li, Yilong; Gould, Andrew; Aboye, Teshome Leta; Bi, Tao; Breindel, Leonard; Shekhtman, Alexander; Camarero, Julio A.

doi:10.1021/acs.jmedchem.6b01689

Cited by 20 publications

(35 citation statements)

References 55 publications

(143 reference statements)

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“…A similar approach was recently used to produce a potent anthrax lethal factor protease inhibitor using the Cys-rich backbone-cyclized θ-defensin RTD-1. [60b] …”

Section: Screening Of Cyclotide-based Librariesmentioning

confidence: 99%

Cyclotides: Overview and Biotechnological Applications

Gould

Camarero

2017

ChemBioChem

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Cyclotides are globular microproteins with a unique head-to-tail cyclized backbone, stabilized by three disulfide bonds forming a cystine knot. This unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to chemical, thermal and biological degradation compared to other peptides of similar size. In addition, cyclotides have been shown to be highly tolerant to sequence variability aside from the conserved residues forming the cystine knot. Cyclotides can also cross cellular membranes and are able to modulate intracellular protein-protein interactions both in vitro and in vivo. All these features make cyclotides appear as highly promising leads or frameworks for the design of peptide-based diagnostic and therapeutic tools. This article provides an overview on cyclotides and their applications as molecular imaging agents and peptide-based therapeutics.

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“…A similar approach was recently used to produce a potent anthrax lethal factor protease inhibitor using the Cys-rich backbone-cyclized θ-defensin RTD-1. [60b] …”

Section: Screening Of Cyclotide-based Librariesmentioning

confidence: 99%

Cyclotides: Overview and Biotechnological Applications

Gould

Camarero

2017

ChemBioChem

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“…To investigate whether “free” RTD-1 in the PsV + RTD-1 mixture contributed to inhibition of HPV16 infection, we used dialysis as a method to take advantage of the size discrepancies between RTD-1 (~2 kDa) and PsVs (>20 megaDa) ( 31 ). After the initial 1 h pre-incubation of virions and RTD-1 we used a large molecular weight membrane to dialyze out unbound RTD-1 prior to PsV collection and addition to cells.…”

Section: Resultsmentioning

confidence: 99%

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering

et al. 2020

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Persistent infection with high-risk human papillomavirus (hrHPV) genotypes results in a large number of anogenital and head and neck cancers worldwide. Although prophylactic vaccination coverage has improved, there remains a need to develop methods that inhibit viral transmission toward preventing the spread of HPV-driven disease. Defensins are a class of innate immune effector peptides that function to protect hosts from infection by pathogens such as viruses and bacteria. Previous work utilizing α and β defensins from humans has demonstrated that the α-defensin HD5 is effective at inhibiting the most common high-risk genotype, HPV16. A third class of defensin that has yet to be explored are θ-defensins: small, 18-amino acid cyclic peptides found in old-world monkeys whose unique structure makes them both highly cationic and resistant to degradation. Here we show that the prototype θ-defensin, rhesus theta defensin 1, inhibits hrHPV infection through a mechanism involving capsid clustering that inhibits virions from binding to cell surface receptor complexes.

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“…The approach described in this work also included an efficient purification procedure to rapidly remove non-folded or partially folded cyclotides from the cyclization-folding crude. This approach can be also employed for the purification of cyclotide mixtures thereby allowing the synthesis of amino acid and positional scanning libraries to perform efficient screening of large chemical-generated libraries (55).…”

Section: Cyclotidesmentioning

confidence: 99%

Using backbone-cyclized Cys-rich polypeptides as molecular scaffolds to target protein–protein interactions

Chaudhuri

Aboye

Camarero

2019

Biochemical Journal

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The use of disulfide-rich backbone-cyclized polypeptides, as molecular scaffolds to design a new generation of bioimaging tools and drugs that are potent and specific, and thus might have fewer side effects than traditional small-molecule drugs, is gaining increasing interest among the scientific and in the pharmaceutical industries. Highly constrained macrocyclic polypeptides are exceptionally more stable to chemical, thermal and biological degradation and show better biological activity when compared with their linear counterparts. Many of these relatively new scaffolds have been also found to be highly tolerant to sequence variability, aside from the conserved residues forming the disulfide bonds, able to cross cellular membranes and modulate intracellular protein–protein interactions both in vitro and in vivo. These properties make them ideal tools for many biotechnological applications. The present study provides an overview of the new developments on the use of several disulfide-rich backbone-cyclized polypeptides, including cyclotides, θ-defensins and sunflower trypsin inhibitor peptides, in the development of novel bioimaging reagents and therapeutic leads.

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Full Sequence Amino Acid Scanning of θ-Defensin RTD-1 Yields a Potent Anthrax Lethal Factor Protease Inhibitor

Cited by 20 publications

References 55 publications

Cyclotides: Overview and Biotechnological Applications

Cyclotides: Overview and Biotechnological Applications

Theta-Defensins Inhibit High-Risk Human Papillomavirus Infection Through Charge-Driven Capsid Clustering

Using backbone-cyclized Cys-rich polypeptides as molecular scaffolds to target protein–protein interactions

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