Design Of Peptides Research Articles

Peptide-based self-assembled monolayers (SAMs): what peptides can do for SAMs and vice versa.

Self-assembled monolayers (SAMs) represent highly ordered molecular materials with versatile biochemical features and multidisciplinary applications. Research on SAMs has made much progress since the early begginings of Au substrates and alkanethiols, and numerous examples of peptide-displaying SAMs can be found in the literature. Peptides, presenting increasing structural complexity, stimuli-responsiveness, and biological relevance, represent versatile functional components in SAMs-based platforms. This review examines the major findings and progress made on the use of peptide building blocks displayed as part of SAMs with specific functions, such as selective cell adhesion, migration and differentiation, biomolecular binding, advanced biosensing, molecular electronics, antimicrobial, osteointegrative and antifouling surfaces, among others. Peptide selection and design, functionalisation strategies, as well as structural and functional characteristics from selected examples are discussed. Additionally, advanced fabrication methods for dynamic peptide spatiotemporal presentation are presented, as well as a number of characterisation techniques. All together, these features and approaches enable the preparation and use of increasingly complex peptide-based SAMs to mimic and study biological processes, and provide convergent platforms for high throughput screening discovery and validation of promising therapeutics and technologies.

Designer pseudopeptides: autofluorescent polygonal tubes via Phe-zipper and triple helix.

Chemists are increasingly turning to biology for inspiration to develop novel and superior synthetic materials. Here, we present an innovative peptide design strategy for tubular assembly. In this simple design, a phenylene urea unit is introduced as an aglet at the N-terminus of the peptide. When α-amino isobutyric acid (Aib) is the first residue and phenylalanine (Phe) is the second residue from the phenylene urea entity, it induces an edge-to-face π-π interaction resulting in a turn conformation. The peptides with a unique reverse turn conformation associate to form polygonal peptide tubes via a Phe-zipper arrangement, as evidenced by microscopic and single crystal X-ray studies. Ultra-microscopic imaging revealed that the tubular assembly is hexagonal, square, and triangular in shape. This hierarchical assembly reveals the interplay between π-π interactions and hydrogen bonding. In another design, pseudopeptide 5, wherein a Phe-Phe (FF) unit is linked to phenylene urea, formed polygonal tubes via a triple helical arrangement. Interestingly, the extension of this design to the bis-urea core resulted in vesicular assembly. These supramolecular polygonal tubes and vesicles showed autofluorescence, which allowed confocal imaging. The observed fluorescence is an additional advantage for applications in biological and medical sciences.

Thioimidates provide general access to thioamide, amidine, and imidazolone peptide-bond isosteres.

Thioamides, amidines, and heterocycles are three classes of modifications that can act as peptide-bond isosteres to alter the peptide backbone. Thioimidate protecting groups can address many of the problematic synthetic issues surrounding installation of these groups. Historically, amidines have received little attention in peptides due to limitations in methods to access them. The first robust and general procedure for the introduction of amidines into peptide backbones exploits the utility of thioimidate protecting groups as a means to side-step reactivity that ultimately renders existing methods unsuitable for the installation of amidines along the main-chain of peptides. Further, amidines formed on-resin can be reacted to form (4H)-imidazolone heteorcycles which have recently been shown to act as cis-amide isosteres. General methods for heterocyclic installation capable of geometrically restricting peptide conformation are also under-developed. This work is significant because it describes a generally applicable and divergent approach to access unexplored peptide designs and architectures.

Multi-CGAN: Deep Generative Model-Based Multiproperty Antimicrobial Peptide Design.

Antimicrobial peptides are peptides that are effective against bacteria and viruses, and the discovery of new antimicrobial peptides is of great importance to human life and health. Although the design of antimicrobial peptides using machine learning methods has achieved good results in recent years, it remains a challenge to learn and design novel antimicrobial peptides with multiple properties of interest from peptide data with certain property labels. To this end, we propose Multi-CGAN, a deep generative model-based architecture that can learn from single-attribute peptide data and generate antimicrobial peptide sequences with multiple attributes that we need, which may have a potentially wide range of uses in drug discovery. In particular, we verified that our Multi-CGAN generated peptides with the desired properties have good performance in terms of generation rate. Moreover, a comprehensive statistical analysis demonstrated that our generated peptides are diverse and have a low probability of being homologous to the training data. Interestingly, we found that the performance of many popular deep learning methods on the antimicrobial peptide prediction task can be improved by using Multi-CGAN to expand the data on the training set of the original task, indicating the high quality of our generated peptides and the robust ability of our method. In addition, we also investigated whether it is possible to directionally generate peptide sequences with specified properties by controlling the input noise sampling for our model.

Antimicrobial activities and mechanisms of truncated and amino-acid-substituted peptides derived from bacteriocin PZJ5

Truncation and amino acid residue substitution are common methods to optimise the design of antimicrobial peptides (AMPs). In the present work, seven truncated and residue-substituted derivatives of Plantaricin ZJ5 (PZJ5) were designed and synthesised. PZJ5-5 was a truncation that simultaneously contained three substituted amino-acid residues, with enhanced antimicrobial activity and low haemolytic activity. The effects of PZJ5-5 on Escherichia coli microstructure were investigated using scanning and transmission electron microscopy, which indicated that its antibacterial mechanism was similar to PZJ5. C-terminal amidation of PZJ5-5 (PZJ5-7) was deleterious, and resulted in a dramatic reduction in potency against E. coli and Listeria monocytogenes, with no potency against the other three indicator bacteria. Truncation and residue substitution of bacteriocin PZJ5 changed its antimicrobial activities and specificities, which provided a rationale for bacteriocin design.

Progressive Design of a Ranatuerin-2 Peptide from Amolops wuyiensis: Enhancement of Bioactivity and In Vivo Efficacy.

Antimicrobial peptides (AMPs) that exert multiple functions are considered promising candidates to combat the bacterial drug resistance crisis. Nowadays, targeted peptide modification has been widely recognised to improve biological activity and make up for deficiencies in clinical applications such as toxicity. In this study, a helix-loop peptide was isolated and identified from the skin secretion of the Wuyi torrent frog Amolops wuyiensis, namely, ranatuerin-2-AW (R2AW) (GFMDTAKNVAKNVAATLLDKLKCKITGGC). Target modifications were made to R2AW to study the structure-activity relationships and to optimise its bioactivities. Five analogues were progressively designed via residue substitution and truncation and the antibacterial and anticancer activities were evaluated. We found that the serine-substitution and cyclic-domain-deletion products showed similar antibacterial activity to the natural peptide R2AW, implying that the disulphide bridge and Rana box were dispensable for the antibacterial activity of ranatuerin-2 peptides. Notably, the cationicity- and hydrophobicity-enhanced variant, [Lys4,19, Leu20]R2AW(1-22)-NH2, exhibited significantly optimised antibacterial and anticancer activities. Additionally, it killed bacteria by membrane disruption at a highly efficient rate. Moreover, [Lys4,19, Leu20]R2AW(1-22)-NH2 exerted potential in vivo efficacy in a methicillin-resistant Staphylococcus aureus (MRSA)-infected waxworm model. Overall, this study demonstrated some rational design ideas for optimising the dual antibacterial and anticancer activities of ranatuerin-2 peptides and it proposes [Lys4,19, Leu20]R2AW(1-22)-NH2 as an appealing candidate for therapeutic development.

Design and Evaluation of a Novel Anti-microbial Peptide from Cathelicidin-2: Selectively Active Against Acinetobacter baumannii.

Infections caused by pathogenic microorganisms have increased the need for hospital care and have thus represented a public health problem and a significant financial burden. Classical treatments consisting of traditional antibiotics face several challenges today. Anti-microbial peptides (AMPs) are a conserved characteristic of the innate immune response among different animal species to defend against pathogenic microorganisms. In this study, a new peptide sequence (mCHTL131-140) was designed using the in silico approach. Cathelicidin-2 (UniprotID: Q2IAL7) was used as a potential antimicrobial protein, and a novel 10 - 12 amino acids sequence AMP was designed using bioinformatics tools and the AMP databases. Then, the anti-bacterial, anti-biofilm, and anti-fungal properties of the peptide, as well as its hemolytic activity and cytotoxicity towards human fibroblast (HDF) cells, were investigated in vitro. Online bioinformatics tools indicated that the peptide sequence could have anti-bacterial, anti-viral, anti-fungal, and anti-biofilm properties with little hemolytic properties. The experimental tests confirmed that mCHTL131-140 exhibited the best anti-bacterial properties against Acinetobacter baumannii and had fair anti-fungal properties. Besides, it did not cause red blood cell lysis and showed no cytotoxicity towards HDF cells. In general, the designed peptide can be considered a promising AMP to control hospital-acquired infections by A. baumannii.

Structural Analysis and Activity Correlation of Amphiphilic Cyclic Antimicrobial Peptides Derived from the [W4R4] Scaffold.

In our ongoing quest to design effective antimicrobial peptides (AMPs), this study aimed to elucidate the mechanisms governing cyclic amphiphilic AMPs and their interactions with membranes. The objective was to discern the nature of these interactions and understand how peptide sequence and structure influence antimicrobial activity. We introduced modifications into the established cyclic AMP peptide, [W4R4], incorporating an extra aromatic hydrophobic residue (W), a positively charged residue (R), or the unique 2,5-diketopiperazine (DKP). This study systematically explored the structure-activity relationships (SARs) of a series of cyclic peptides derived from the [W4R4] scaffold, including the first synthesis and evaluation of [W4R4(DKP)]. Structural, dynamic, hydrophobic, and membrane-binding properties of four cyclic peptides ([W4R4], [W5R4], [W4R5], [W4R4(DKP)]) were explored using molecular dynamics simulations within a DOPC/DOPG lipid bilayer that mimics the bacterial membrane. The results revealed distinct SARs linking antimicrobial activity to parameters such as conformational plasticity, immersion depth in the bilayer, and population of the membrane binding mode. Notably, [W4R5] exhibited an optimal "activity/binding to the bacterial membrane" pattern. This multidisciplinary approach efficiently decoded finely regulated SAR profiles, laying a foundation for the rational design of novel antimicrobial peptides.

Design, synthesis and bioactivity evaluation of novel fusion peptides and their CPT conjugates inducing effective anti-tumor responses on HER2 positive tumors

Human epidermal growth factor receptor 2 (HER2) represents an ideal target for antibody drug development, abnormal expression of the HER2 gene is associated with multiple tumor types. Pertuzumab, as the first monoclonal antibody inhibitor of HER2 dimerization, has been FDA-approved for HER2-positive patients. In order to enhance the activity of HER2-targeted peptide-drug conjugates (PDCs) developed based on pertuzumab, a novel class of conjugates 1–9 was designed and synthesized by fusing the N-terminal peptide sequence of the second mitochondria-derived activator of caspases (SMAC) with P1, followed by conjugation with CPT molecules. Compound 4 exhibited excellent in vitro anti-tumor activity across the three HER2-positive cell lines, comparable to the activity of CPT. Apoptosis induction assays indicated that the synergistic effect of the SMAC sequence enhanced the pro-apoptotic activity of the conjugate. Western Blot analysis and Caspase activity studies validated the mechanism through which SMAC peptides, in synergy with CPT, enhance the activity of PDCs. In vivo studies demonstrated that compound 4 possesses superior anti-tumor activity compared to CPT and can effectively mitigate potential renal toxicity associated with free SMAC peptides. In conclusion, conjugate 4 exhibited excellent anti-tumor activity both in vitro and in vivo, offering potential for further development as a novel peptide-conjugated drug.

Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor

Despite the increasing number of GPCR structures and recent advances in peptide design, the development of efficient technologies allowing rational design of high-affinity peptide ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach for designing conjugates of lariat-shaped macrocyclized peptides and a small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds for the kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit in vitro potent mixed KOR agonism/mu-opioid receptor (MOR) antagonism, nanomolar binding affinity, selectivity, and efficacy bias at KOR. Proof-of-concept in vivo efficacy studies demonstrate that DNCP-β-NalA(1) induces a potent KOR-mediated antinociception in male mice. The high-resolution cryo-EM structure (2.6 Å) of the DNCP-β-NalA–KOR–Gi1 complex and molecular dynamics simulations are harnessed to validate the computational design model. This reveals a network of residues in ECL2/3 and TM6/7 controlling the intrinsic efficacy of KOR. In general, our computational de novo platform overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may drive the development of next-generation therapeutics for medical applications such as pain conditions.

Abstract C118: Design of programmable peptide-guided oncoprotein degraders via generative language models

Abstract Targeted protein degradation of pathogenic proteins represents a powerful new treatment strategy for multiple cancers. Unfortunately, a sizable portion of these proteins are considered “undruggable” by standard small molecule-based approaches, including PROTACs and molecular glues, largely due to their disordered nature, instability, and lack of binding site accessibility. As a more modular strategy, we have developed a genetically-encoded protein architecture by fusing target-specific peptides to E3 ubiquitin ligase domains for selective and potent intracellular degradation of oncoproteins. To enable programmability of our system, we develop a suite of algorithms that enable the design of target-specific peptides via protein language model (pLM) embeddings, without the requirement of 3D structures. First, we train a model that leverages pLM embeddings to efficiently select high-affinity peptides from natural protein interaction interfaces. Next, we develop a high-accuracy discriminator, based on the contrastive language-image pretraining (CLIP) architecture underlying OpenAI's DALL-E model, to prioritize and screen peptides with selectivity to a specified target oncoprotein. As input to the discriminator, we create a Gaussian diffusion generator to sample a pLM latent space, fine-tuned on experimentally-valid peptide sequences. Finally, to enable de novo design of binding peptides, we train an instance of GPT-2 with protein interacting sequences to enable peptide generation conditioned on target oncoprotein sequences. Our models demonstrate low perplexities across both existing and generated peptide sequences, highlighting their robust generative capability. By experimentally fusing model-derived peptides to E3 ubiquitin ligase domains, we reliably identify candidates exhibiting robust and selective endogenous degradation of diverse, "undruggable" oncoproteins in cancer cell models, including tumorigenic regulators such as β-catenin and TRIM8, as well as oncogenic fusion proteins, such as EWS-FLI1, PAX3-FOXO1, and DNAJB1-PRKACA. We further show that our peptide-guided degraders have negligible off-target effects via whole-cell proteomics and demonstrate their modulation of transcriptional and apoptotic pathways, motivating further translation of our therapeutic platform. Together, our work establishes a CRISPR-analogous system for programmable protein degradation applications across the oncoproteome. Citation Format: Suhaas Bhat, Garyk Brixi, Kalyan Palepu, Lauren Hong, Vivian Yudistyra, Tianlai Chen, Sophia Vincoff, Lin Zhao, Pranam Chatterjee. Design of programmable peptide-guided oncoprotein degraders via generative language models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C118.

Development and Evaluation of the Efficacy and Toxicity of a New Hybrid Antimicrobial Peptide MY8.

Antibiotics have led to significant advancements in medicine. Unfortunately, they were faced with the emergence of pathogen resistance. According to the World Health Organization, antimicrobial resistance has been declared one of humanity's top ten global public health threats. The risk of those bacteria is not only from their being resistant to multi-antibiotics but also from their ability to form biofilms, which can be 1,000 times more resistant than planktonic bacteria. This study used rational design to hybridize two antimicrobial peptides, aiming to enhance their efficacy and stability with reduced toxicity. The MY8 novel peptide was designed from the parent peptides BMAP-27 and CAMP 211-225. Some amino acid modifications were introduced to the hybrid peptide to improve its physicochemical properties guided by several software. Its antimicrobial activity has been studied against gram-negative and gram-positive strains, which showed broad-spectrum activity with MIC values against planktonic bacteria ranging from 0.125 to 25 μM. In contrast, 25-200 μM were needed to eradicate biofilms. Moreover, the MY8 peptide showed synergism with four conventional antibiotics., It also showed reduced toxicity against mammalian cells and a slight hemolysis tendency towards erythrocytes. The design of the MY8 peptide was successful, resulting in a novel, potent, broad-spectrum antimicrobial peptide with reduced toxicity and possible synergism with conventional antibiotics.

Photoresponsive peptide materials: Spatiotemporal control of self-assembly and biological functions.

Peptides work as both functional molecules to modulate various biological phenomena and self-assembling artificial materials. The introduction of photoresponsive units to peptides allows the spatiotemporal remote control of their structure and function upon light irradiation. This article overviews the photoresponsive peptide design, interaction with biomolecules, and applications in self-assembling materials over the last 30 years. Peptides modified with photochromic (photoisomerizable) molecules, such as azobenzene and spiropyran, reversibly photo-controlled the binding to biomolecules and nanostructure formation through self-assembly. Photocleavable molecular units irreversibly control the functions of peptides through cleavage of the main chain and deprotection by light. Photocrosslinking between peptides or between peptides and other biomolecules enhances the structural stability of peptide assemblies and complexes. These photoresponsive peptides spatiotemporally controlled the formation and dissociation of peptide assemblies, gene expressions, protein-drug interactions, protein-protein interactions, liposome deformation and motility, cytoskeleton structure and stability, and cell functions by appropriate light irradiation. These molecular systems can be applied to photo-control biological functions, molecular robots, artificial cells, and next-generation smart drug delivery materials.

Multiscale Simulations to Discover Self-Assembled Oligopeptides: A Benchmarking Study.

Peptide self-assembly is critical for biomedical and material discovery and production. While it is costly to experimentally test every possible peptide design, computational assessment provides an affordable solution to evaluate many designs and prioritize synthesis and characterization. Following a theoretical investigation, we present a systematic analysis of all-atom and coarse-grained simulations to predict peptide self-assembly. Benchmarking studies of two model dipeptides allow us to assess the impacts of intrinsic properties (such as amino acids and terminal modifications) and external environment (such as salinity) on the simulated aggregation. Further examination of 20 oligopeptides containing two to five amino acids shows good agreement among our theory, simulations, and prior experimental observations. The success rate of our prediction is 90%. Therefore, our theory, simulation, and analysis can be useful to identify peptide designs that can self-assemble and predict the potential nanostructures. These findings lay the ground for future virtual screening of peptide-assembled nanostructures and computer-aided biologics design.

Design of MERS-CoV entry inhibitory short peptides based on helix-stabilizing strategies

Interaction between Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) protein heptad repeat-1 domain (HR1) and heptad repeat-2 domain (HR2) is critical for the MERS-CoV fusion process. This interaction is mediated by the α-helical region from HR2 and the hydrophobic groove in a central HR1 trimeric coiled coil. We sought to develop a short peptidomimetic to act as a MERS-CoV fusion inhibitor by reproducing the key recognition features of HR2 helix. This was achieved by the use of helix-stabilizing strategies, including substitution with unnatural helix-favoring amino acids, introduction of ion pair interactions, and conjugation of palmitic acid. The resulting 23-mer lipopeptide, termed AEEA-C16, inhibits MERS-CoV S protein-mediated cell–cell fusion at a low micromolar level comparable to that of the 36-mer HR2 peptide HR2P-M2. Collectively, our studies provide new insights into developing short peptide-based antiviral agents to treat MERS-CoV infection.

Integrative Proteogenomics for Differential Expression and Splicing Variation in a DM1 Mouse Model

Dysregulated mRNA splicing is involved in the pathogenesis of many diseases including cancer, neurodegenerative diseases, and muscular dystrophies such as myotonic dystrophy type 1 (DM1). Comprehensive assessment of dysregulated splicing on the transcriptome and proteome level has been methodologically challenging, and thus investigations have often been targeting only few genes. Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNAs and proteins. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g., Atp2a1, Bin1, Ryr1), complemented by novel findings (Flnc and Ywhae). Comparative analysis of large-scale mRNA and protein expression data showed quantitative agreement of differentially expressed genes and splicing patterns between disease and wild type. We hence propose this work as a suitable blueprint for a robust and scalable integrative proteogenomic strategy geared toward advancing our understanding of splicing-based disorders. With such a strategy, splicing-based biomarker candidates emerge as an attractive and accessible option, as they can be efficiently asserted on the mRNA and protein level in coordinated fashion.

Design and evaluation of tadpole-like conformational antimicrobial peptides

Antimicrobial peptides are promising alternatives to conventional antibiotics. Herein, we report a class of “tadpole-like” peptides consisting of an amphipathic α-helical head and an aromatic tail. A structure-activity relationship (SAR) study of “tadpole-like” temporin-SHf and its analogs revealed that increasing the number of aromatic residues in the tail, introducing Arg to the α-helical head and rearranging the peptide topology dramatically increased antimicrobial activity. Through progressive structural optimization, we obtained two peptides, HT2 and RI-HT2, which exhibited potent antimicrobial activity, no hemolytic activity and cytotoxicity, and no propensity to induce resistance. NMR and molecular dynamics simulations revealed that both peptides indeed adopted “tadpole-like” conformations. Fluorescence experiments and electron microscopy confirmed the membrane targeting mechanisms of the peptides. Our studies not only lead to the discovery of a series of ultrashort peptides with potent broad-spectrum antimicrobial activities, but also provide a new strategy for rational design of novel “tadpole-like” antimicrobial peptides.

Cell-free biosynthesis combined with deep learning accelerates de novo-development of antimicrobial peptides

Bioactive peptides are key molecules in health and medicine. Deep learning holds a big promise for the discovery and design of bioactive peptides. Yet, suitable experimental approaches are required to validate candidates in high throughput and at low cost. Here, we established a cell-free protein synthesis (CFPS) pipeline for the rapid and inexpensive production of antimicrobial peptides (AMPs) directly from DNA templates. To validate our platform, we used deep learning to design thousands of AMPs de novo. Using computational methods, we prioritized 500 candidates that we produced and screened with our CFPS pipeline. We identified 30 functional AMPs, which we characterized further through molecular dynamics simulations, antimicrobial activity and toxicity. Notably, six de novo-AMPs feature broad-spectrum activity against multidrug-resistant pathogens and do not develop bacterial resistance. Our work demonstrates the potential of CFPS for high throughput and low-cost production and testing of bioactive peptides within less than 24 h.

A methodological approach by capillary electrophoresis coupled to mass spectrometry via electrospray interface for the characterization of short synthetic peptides towards the conception of self-assembled nanotheranostic agents

Nanostructures formed by the self-assembling peptide building blocks are attractive materials for the design of theranostic objects due to their intrinsic biocompatibility, accessible surface chemistry as well as cavitary morphology. Short peptide synthesis and modification are straightforward and give access to a great diversity of sequences, making them very versatile building blocks allowing for the design of thoroughly controlled self-assembled nanostructures. In this work, we developed a new CE-DAD-ESI-MS method to characterize short synthetic amphiphilic peptides in terms of exact sequence and purity level in the low 0.1 mg.mL−1 range, without sample treatment. This study was conducted using a model sequence, described to have pH sensitive self-assembling property. Peptide samples obtained from different synthesis processes (batch or flow, purified or not) were thus separated by capillary zone electrophoresis (CZE). The associated dual UV and MS detection mode allowed to evidence the exact sequence together with the presence of impurities, identified as truncated or non-deprotected sequences, and to quantify their relative proportion in the peptide mixture. Our results demonstrate that the developed CE-DAD-ESI-MS method could be directly applied to the characterization of crude synthetic peptide products, in parallel with the optimization of peptide synthetic pathway to obtain controlled sequences with high synthetic yield and purity, which is crucial for further design of robust peptide based self-assembled nanoarchitectures.

Candida albicans and Antifungal Peptides.

Candida albicans, a ubiquitous opportunistic fungal pathogen, plays a pivotal role in human health and disease. As a commensal organism, it normally resides harmlessly within the human microbiota. However, under certain conditions, C.albicans can transition into a pathogenic state, leading to various infections collectively known as candidiasis. With the increasing prevalence of immunocompromised individuals and the widespread use of invasive medical procedures, candidiasis has become a significant public health concern. The emergence of drug-resistant strains further complicates treatment options, highlighting the urgent need for alternative therapeutic strategies. Antifungal peptides (AFPs) have gained considerable attention as potential candidates for combating Candida spp. infections. These naturally occurring peptides possess broad-spectrum antimicrobial activity, including specific efficacy against C.albicans. AFPs exhibit several advantageous properties, such as rapid killing kinetics, low propensity for resistance development, and diverse mechanisms of action, making them promising alternatives to conventional antifungal agents. In recent years, extensive research has focused on discovering and developing novel AFPs with improved efficacy and selectivity against Candida species. Advances in biotechnology and synthetic peptide design have enabled the modification and optimization of natural peptides, enhancing their stability, bioavailability, and therapeutic potential. Nevertheless, several challenges must be addressed before AFPs can be widely implemented in clinical practice. These include optimizing peptide stability, enhancing delivery methods, overcoming potential toxicity concerns, and conducting comprehensive preclinical and clinical studies. This commentary presents a short overview of candidemia and AFP; articles and reviews published in the last 10years were searched on The National Library of Medicine (National Center for Biotechnology Information-NIH-PubMed). The terms used were C.albicans infections, antimicrobial peptides, antifungal peptides, antifungal peptides mechanisms of action, candidemia treatments and guidelines, synthetic peptides and their challenges, and antimicrobial peptides in clinical trials as the main ones. Older publications were cited if they brought some relevant concept or helped to bring a perspective into our narrative. Articles older than 20years and those that appeared in PubMed but did not match our goal to bring updated information about using antifungal peptides as an alternative to C.albicans infections were not considered.