Reprogramming biological peptides to combat infectious diseases

Torres, Marcelo Der Torossian; Fuente-Núñez, César de la

doi:10.1039/c9cc07898c

Cited by 47 publications

(36 citation statements)

References 126 publications

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“…However, the development of AMPs has been limited by the lack of methods for cost‐effective 38 and rational 39 design. Although some alternative methods to overcome these limitations have been proposed, 2,3 we are far from understanding the structure–activity relationship (SAR) of these agents, which would provide a more substantial basis for their rational design and accelerate their translation into the clinic.…”

Section: Resultsmentioning

confidence: 99%

“…The role of peptides as antimicrobial agents has been extensively described in the literature 1‐5 . New strategies for the design and development of these molecules, 6‐8 combined with the rising resistance of microorganisms to standard antibiotics, 9,10 are boosting worldwide interest and studies on antimicrobial peptides (AMPs).…”

Section: Figurementioning

confidence: 99%

“…The role of peptides as antimicrobial agents has been extensively described in the literature. [1][2][3][4][5] New strategies for the design and development of these molecules, [6][7][8] combined with the rising resistance of microorganisms to standard antibiotics, 9,10 are boosting worldwide interest and studies on antimicrobial peptides (AMPs). For example, recent reports have described the design of AMPs with broadspectrum activity, particularly amphipathic cationic peptides.…”

Section: Introductionmentioning

confidence: 99%

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The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

Torres

Silva

Andrade

et al. 2020

Bioengineering & Transla Med

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The wasp venom-derived antimicrobial peptide polybia-CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical-guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia-CP and derivatives, namely their ability to target Plasmodium sporozoites and cancer cells. We leverage a physicochemical-guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity-related properties of polybia-CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia-CP and analogs. Additionally, we demonstrate that a physicochemical-guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure-function to generate novel and potent new-to-nature therapies. Cesar de la Fuente-Nunez holds a Presidential Professorship at the University of Pennsylvania, is a recipient of the Langer Prize by the AIChE Foundation and acknowledges funding from the

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

Torres

Silva

Andrade

et al. 2020

Bioengineering & Transla Med

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“…Hence, using PRA, a library of synthetic peptides, based on the sequence of indolicidin, was generated with specificity to VEEV and potentially other alphaviruses. Computational-based approaches to designing peptides can be used to generate synthetic versions that are more ideal than the natural templates used for design 35,36 . www.nature.com/scientificreports/ Algorithm tools utilize biological and chemical properties that are known to influence activity of peptides such as sequence length, net charge, and hydrophobicity 35 .…”

Section: Discussionmentioning

confidence: 99%

“…Computational-based approaches to designing peptides can be used to generate synthetic versions that are more ideal than the natural templates used for design 35,36 . www.nature.com/scientificreports/ Algorithm tools utilize biological and chemical properties that are known to influence activity of peptides such as sequence length, net charge, and hydrophobicity 35 . These factors along with other computational biology approaches and method-based strategies allow for the generation and selection of a large number of peptides designed with pathogen specificity.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Host Defense Peptides Inhibit Venezuelan Equine Encephalitis Virus Replication and the Associated Inflammatory Response

Ahmed

Bakovic

Risner

et al. 2020

Sci Rep

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Venezuelan equine encephalitis virus (VEEV), a New World alphavirus of the Togaviridae family of viruses causes periodic outbreaks of disease in humans and equines. Disease following VEEV infection manifests as a febrile illness with flu-like symptoms, which can progress to encephalitis and cause permanent neurological sequelae in a small number of cases. VEEV is classified as a category B select agent due to ease of aerosolization and high retention of infectivity in the aerosol form. Currently, there are no FDA-approved vaccines or therapeutics available to combat VEEV infection. VEEV infection in vivo is characterized by extensive systemic inflammation that can exacerbate infection by potentially increasing the susceptibility of off-site cells to infection and dissemination of the virus. Hence, a therapeutic targeting both the infection and associated inflammation represents an unmet need. We have previously demonstrated that host defense peptides (HDPs), short peptides that are key components of the innate immune response, exhibit antiviral activity against a multitude of viruses including VEEV. In this study, we designed synthetic peptides derived from indolicidin, a naturally occurring HDP, and tested their efficacy against VEEV. Two candidate synthetic peptides inhibited VEEV replication by approximately 1000-fold and decreased the expression of inflammatory mediators such as IL1α, IL1β, IFNγ, and TNFα at both the gene and protein expression levels. Furthermore, an increase in expression levels of genes involved in chemotaxis of leukocytes and anti-inflammatory genes such as IL1RN was also observed. Overall, we conclude that our synthetic peptides inhibit VEEV replication and the inflammatory burden associated with VEEV infection.

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Challenges in computational discovery of bioactive peptides in ’omics data

Coelho,

Santos‐Júnior,

de la Fuente‐Nunez

2024

Proteomics

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Peptides have a plethora of activities in biological systems that can potentially be exploited biotechnologically. Several peptides are used clinically, as well as in industry and agriculture. The increase in available ’omics data has recently provided a large opportunity for mining novel enzymes, biosynthetic gene clusters, and molecules. While these data primarily consist of DNA sequences, other types of data provide important complementary information. Due to their size, the approaches proven successful at discovering novel proteins of canonical size cannot be naïvely applied to the discovery of peptides. Peptides can be encoded directly in the genome as short open reading frames (smORFs), or they can be derived from larger proteins by proteolysis. Both of these peptide classes pose challenges as simple methods for their prediction result in large numbers of false positives. Similarly, functional annotation of larger proteins, traditionally based on sequence similarity to infer orthology and then transferring functions between characterized proteins and uncharacterized ones, cannot be applied for short sequences. The use of these techniques is much more limited and alternative approaches based on machine learning are used instead. Here, we review the limitations of traditional methods as well as the alternative methods that have recently been developed for discovering novel bioactive peptides with a focus on prokaryotic genomes and metagenomes.

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Reprogramming biological peptides to combat infectious diseases

Abstract: With the rapid spread of resistance among pathogens, novel approaches such as engineering synthetic antimicrobial peptides represent promising alternatives to currently available antibiotics.

Cited by 47 publications

References 126 publications

The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

Synthetic Host Defense Peptides Inhibit Venezuelan Equine Encephalitis Virus Replication and the Associated Inflammatory Response

Challenges in computational discovery of bioactive peptides in ’omics data

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