Structural determinants conferring unusual long life in human serum to rattlesnake-derived antimicrobial peptide Ctn[15-34].

Published on Aug 1, 2019in Journal of Peptide Science1.877
· DOI :10.1002/PSC.3195
Clara Pérez-Peinado6
Estimated H-index: 6
(Barcelona Biomedical Research Park),
Susana A. Dias6
Estimated H-index: 6
(IMM: Instituto de Medicina Molecular)
+ 3 AuthorsDavid Andreu70
Estimated H-index: 70
(Barcelona Biomedical Research Park)
Sources
Abstract
: Ctn[15-34], a downsized version of the snake venom cathelicidin-like peptide crotalicidin (Ctn), shows an unusually high lifespan (t1/2 , approximately 12 h) in human serum, which significantly adds to its promise as an antimicrobial and antitumor agent. Herein we investigate the role of Ctn[15-34] structure on serum survival. Using a set of analogs, we show that C-terminal amidation, as well as the specific layout of the Ctn[15-34] sequence-a helical N-terminal domain followed by a hydrophobic domain-is crucial for slow degradation, and any change in their arrangement results in significantly lower t1/2 . Aside from the privileged primary structure, features such as self-aggregation can be ruled out as causes for the long serum life. Instead, studies in other protease-rich fluids suggest a key role for certain human serum components. Finally, we demonstrate that Ctn[15-34] is able to induce bacterial death even after 12-hour pre-incubation in serum, in agreement with the proteolytic data. Altogether, the results shed light on the uncommon stability of Ctn[15-34] in human serum and confirm its potential as an anti-infective lead.
References50
Newest
#1Clara Pérez-Peinado (Barcelona Biomedical Research Park)H-Index: 6
#2Sira Defaus (Barcelona Biomedical Research Park)H-Index: 7
Last. David Andreu (Barcelona Biomedical Research Park)H-Index: 70
view all 5 authors...
Abstract The inherent propensity to enzymatic degradation of most peptides remains a bottleneck in their therapeutic development. Efficient, early screening methods are necessary for in vitro characterization of the molecular events occurring when peptides get in contact with biological fluids such us plasma. Herein we present an affinity purification/MS approach for mapping peptide serum interactors. We have applied this methodology to identify the serum partners of antibiotic peptide Ctn [15-3...
5 CitationsSource
#1Tiago N. Figueira (IMM: Instituto de Medicina Molecular)H-Index: 7
#2Diogo A. Mendonça (IMM: Instituto de Medicina Molecular)H-Index: 2
Last. Ana Salomé Veiga (IMM: Instituto de Medicina Molecular)H-Index: 19
view all 8 authors...
Measles remains one of the leading causes of child mortality worldwide and is re-emerging in some countries due to poor vaccine coverage, concomitant with importation of measles virus (MV) from endemic areas. The lack of specific chemotherapy contributes to negative outcomes, especially in infants or immunodeficient individuals. Fusion inhibitor peptides derived from the MV Fusion protein C-terminal Heptad Repeat (HRC) targeting MV envelope fusion glycoproteins block infection at the stage of en...
7 CitationsSource
#1Miloš Erak (Leipzig University)H-Index: 1
#2Kathrin Bellmann-Sickert (Leipzig University)H-Index: 12
Last. Annette G. Beck-Sickinger (Leipzig University)H-Index: 76
view all 4 authors...
Abstract The development of solid phase peptide synthesis has released tremendous opportunities for using synthetic peptides in medicinal applications. In the last decades, peptide therapeutics became an emerging market in pharmaceutical industry. The need for synthetic strategies in order to improve peptidic properties, such as longer half-life, higher bioavailability, increased potency and efficiency is accordingly rising. In this mini-review, we present a toolbox of modifications in peptide c...
74 CitationsSource
#1Prashant Kumar (UBC: University of British Columbia)H-Index: 7
#2Jayachandran N. Kizhakkedathu (UBC: University of British Columbia)H-Index: 50
Last. Suzana K. Straus (UBC: University of British Columbia)H-Index: 29
view all 3 authors...
Antibiotic resistance is projected as one of the greatest threats to human health in the future and hence alternatives are being explored to combat resistance. Antimicrobial peptides (AMPs) have shown great promise, because use of AMPs leads bacteria to develop no or low resistance. In this review, we discuss the diversity, history and the various mechanisms of action of AMPs. Although many AMPs have reached clinical trials, to date not many have been approved by the US Food and Drug Administrat...
279 CitationsSource
#1Clara Pérez-Peinado (Barcelona Biomedical Research Park)H-Index: 6
#2Susana A. Dias (IMM: Instituto de Medicina Molecular)H-Index: 6
Last. David Andreu (Barcelona Biomedical Research Park)H-Index: 70
view all 12 authors...
Crotalicidin (Ctn), a cathelicidin-related peptide from the venom of a South American rattlesnake, possesses potent antimicrobial, antitumor, and antifungal properties. Previously, we have shown that its C-terminal fragment, Ctn[15-34], retains the antimicrobial and antitumor activities, but is less toxic to healthy cells and has improved serum stability. Here, we investigated the mechanism of action of Ctn and Ctn[15-34] against gram-negative bacteria. Both peptides were bactericidal, killing ~...
36 CitationsSource
25 CitationsSource
#1Annarita Falanga (University of Naples Federico II)H-Index: 33
#2Ersilia NigroH-Index: 19
Last. Olga ScudieroH-Index: 21
view all 7 authors...
Cyclic peptides are receiving significant attention thanks to their antimicrobial activity and high serum stability, which is useful to develop and design novel antimicrobial agents. Antimicrobial peptides appear to be key components of innate defences against bacteria, viruses, and fungi. Among the others, defensins possess a strong microbicidial activity. Defensins are cationic and amphipathic peptides with six cysteine residues connected by three disulfide bonds found in plants, insects, and ...
41 CitationsSource
#1Josep M. Sierra (University of Barcelona)H-Index: 23
#2Ester Fusté (University of Barcelona)H-Index: 9
Last. Miguel Viñas (University of Barcelona)H-Index: 23
view all 5 authors...
ABSTRACTIntroduction: The recent dramatic increase in the incidence of antimicrobial resistance has been recognized by organizations such as the United Nations and World Health Organization as well as the governments of the USA and several European countries. A relatively new weapon in the fight against severe infections caused by multi-drug resistant bacteria is antimicrobial peptides (AMPs). These include colistin, currently regarded as the last line of antimicrobial therapy against multi-drug...
129 CitationsSource
#1Randi Nordström (Uppsala University)H-Index: 9
#2Martin Malmsten (Uppsala University)H-Index: 74
Due to rapidly increasing resistance development against conventional antibiotics, finding novel approaches for the treatment of infections has emerged as a key health issue. Antimicrobial peptides ...
93 CitationsSource
#1Carolina Sidrim de Paula Cavalcante (UPF: Pompeu Fabra University)H-Index: 5
#2Cláudio Borges Falcão (UFC: Federal University of Ceará)H-Index: 9
Last. Gandhi Rádis-Baptista (UFC: Federal University of Ceará)H-Index: 19
view all 5 authors...
Anti-fungal activity of Ctn[15–34], the C-terminal peptide fragment of crotalicidin, a rattlesnake venom gland cathelicidin
17 CitationsSource
Cited By6
Newest
#1Marco Cavaco (UPF: Pompeu Fabra University)
#1Marco Cavaco (IMM: Instituto de Medicina Molecular)
Last. Miguel A. R. B. Castanho (IMM: Instituto de Medicina Molecular)H-Index: 49
view all 5 authors...
Proteolytic instability is a critical limitation for peptide-based products. Although significant efforts are devoted to stabilize sequences against proteases/peptidases in plasma/serum, such approaches tend to be rather empirical, unspecific, time-consuming, and frequently not cost-effective. A more rational and potentially rewarding alternative is to identify the chemical grounds of susceptibility to enzymatic degradation of peptides so that proteolytic resistance can be tuned by manipulation ...
Source
#2Nuno C. Santos (IMM: Instituto de Medicina Molecular)H-Index: 42
Last. Sónia GonçalvesH-Index: 17
view all 6 authors...
Ctn[15-34], the C-terminal fragment of crotalicidin, an antimicrobial peptide from the South American rattlesnake Crotalus durissus terrificus venom, displays remarkable anti-infective and anti-proliferative activities. Herein, its activity on Candida albicans biofilms and its interaction with the cytoplasmic membrane of the fungal cell and with a biomembrane model in vitro was investigated. A standard C. albicans strain and a fluconazole-resistant clinical isolate were exposed to the peptide at...
3 CitationsSource
#1Clara Pérez-Peinado (Barcelona Biomedical Research Park)H-Index: 6
#2Javier Valle (Barcelona Biomedical Research Park)H-Index: 8
Last. David Andreu (Barcelona Biomedical Research Park)H-Index: 70
view all 4 authors...
Crotalicidin (Ctn) and its fragment Ctn[15-34] are snake-venom-derived, cathelicidin-related peptides outstanding for their promising antimicrobial, antifungal, and antitumoral properties. In this study, we describe their membranolytic mechanisms as well as their putative interference with intracellular targets, both contributing to their antitumoral action against a pro-monocytic leukemia cell line. Initial flow cytometry assays demonstrated peptide ability to induce tumor cell membrane permeab...
1 CitationsSource
#1Anna Maystrenko (U of G: University of Guelph)
#2Yulong Feng (U of G: University of Guelph)
Last. Julang Li (U of G: University of Guelph)H-Index: 26
view all 4 authors...
Multi-drug resistant (MDR) bacteria and their biofilms are a concern in veterinary and human medicine. Protegrin-1 (PG-1), a potent antimicrobial peptide (AMP) with antimicrobial and immunomodulatory properties, is considered a potential alternative for conventional antibiotics. AMPs are less stable and lose activity in the presence of physiological fluids, such as serum. To improve stability of PG-1, a hybrid peptide, SynPG-1, was designed. The antimicrobial and antibiofilm properties of PG-1 a...
2 CitationsSource
#1Clara Pérez-Peinado (Barcelona Biomedical Research Park)H-Index: 6
#2Sira Defaus (Barcelona Biomedical Research Park)H-Index: 7
Last. David Andreu (Barcelona Biomedical Research Park)H-Index: 70
view all 3 authors...
For decades, natural products in general and snake venoms (SV) in particular have been a rich source of bioactive compounds for drug discovery, and they remain a promising substrate for therapeutic development. Currently, a handful of SV-based drugs for diagnosis and treatment of various cardiovascular disorders and blood abnormalities are on the market. Likewise, far more SV compounds and their mimetics are under investigation today for diverse therapeutic applications, including antibiotic-res...
10 CitationsSource
#1Cláudio Borges Falcão (UFC: Federal University of Ceará)H-Index: 9
#2Gandhi Rádis-Baptista (UFC: Federal University of Ceará)H-Index: 19
Abstract A global public health crisis has emerged with the extensive dissemination of multidrug-resistant microorganisms. Antimicrobial peptides (AMPs) from plants and animals have represented promising tools to counteract those resistant pathogens due to their multiple pharmacological properties such as antimicrobial, anticancer, immunomodulatory and cell-penetrating activities. In this review, we will focus on crotamine and crotalicidin, which are two interesting examples of membrane active p...
4 CitationsSource
#1F.L.L. de Aguiar (UFC: Federal University of Ceará)H-Index: 1
#2Carolina Sidrim de Paula Cavalcante (State University of Ceará)H-Index: 5
Last. Gandhi Rádis-Baptista (UFC: Federal University of Ceará)H-Index: 19
view all 6 authors...
AIMS: Crotalicidin (Ctn), a cathelicidin-related antimicrobial peptide from the South American rattlesnake venom gland, and its C-terminal Ctn[15-34] fragment, have exhibited important activities against micro-organisms, trypanosomatid protozoa and certain lines of tumour cells. Herein, the activity against clinical strains of fluconazole-resistant Candida albicans and of amphotericin B and fluconazole-resistant Cryptococcus neoformans was investigated. METHODS AND RESULTS: Microdilution and lum...
5 CitationsSource