Peptides to Tackle Leishmaniasis: Current Status and Future Directions

Robles-Loaiza, Alberto A; Pinos-Tamayo, Edgar A.; Mendes, Bruno; Teixeira, Cátia; Alves, Cláudia; Gomes, Paula; Almeida, José R.

doi:10.3390/ijms22094400

Cited by 20 publications

(16 citation statements)

References 108 publications

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“…Peptide drugs constitute an emerging therapy occupying a prominent market niche in the pharmaceutical industry trends [27,28]. The peptide therapeutics market is progressing with very favorable prospects, recognized potential, recent successful approvals by regulatory agencies and economic expansion [2].…”

Section: Discussionmentioning

confidence: 99%

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Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A2-Derived Peptides

Almeida

Mendes

Lancellotti

et al. 2021

CIMB

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The membrane-active nature of phospholipase A2-derived peptides makes them potential candidates for antineoplastic and antibacterial therapies. Two short 13-mer C-terminal fragments taken from snake venom Lys49-PLA2 toxins (p-AppK and p-Acl), differing by a leucine/phenylalanine substitution, were synthesized and their bioactivity was evaluated. Their capacity to interfere with the survival of Gram-positive and Gram-negative bacteria as well as with solid and liquid tumors was assessed in vitro. Toxicity to red blood cells was investigated via in silico and in vitro techniques. The mode of action was mainly studied by molecular dynamics simulations and membrane permeabilization assays. Briefly, both peptides have dual activity, i.e., they act against both bacteria, including multidrug-resistant strains and tumor cells. All tested bacteria were susceptible to both peptides, Pseudomonas aeruginosa being the most affected. RAMOS, K562, NB4, and CEM cells were the main leukemic targets of the peptides. In general, p-Acl showed more significant activity, suggesting that phenylalanine confers advantages to the antibacterial and antitumor mechanism, particularly for osteosarcoma lines (HOS and MG63). Peptide-based treatment increased the uptake of a DNA-intercalating dye by bacteria, suggesting membrane damage. Indeed, p-AppK and p-Acl did not disrupt erythrocyte membranes, in agreement with in silico predictions. The latter revealed that the peptides deform the membrane and increase its permeability by facilitating solvent penetration. This phenomenon is expected to catalyze the permeation of solutes that otherwise could not cross the hydrophobic membrane core. In conclusion, the present study highlights the role of a single amino acid substitution present in natural sequences towards the development of dual-action agents. In other words, dissecting and fine-tuning biomembrane remodeling proteins, such as snake venom phospholipase A2 isoforms, is again demonstrated as a valuable source of therapeutic peptides.

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Section: Discussionmentioning

confidence: 99%

“…Although red blood cells are considered a classical model for the initial assessment of peptide toxicity, further works should consider the use of other healthy cells. The tunability and simple peptide synthesis enable an easy fine-tuning, which contributes to selectivity and generation of safer and efficient analogues [28].…”

Section: Discussionmentioning

confidence: 99%

Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A2-Derived Peptides

Almeida

Mendes

Lancellotti

et al. 2021

CIMB

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“…Many bibliographic studies have covered the therapeutic effects of peptides in the most diverse areas [ 41 , 42 , 43 , 44 ], including the discussion of market trends, current challenges, and prospects [ 1 , 5 , 45 ]. On the other hand, several reviews have recently highlighted the development of in silico methods to support the discovery of antimicrobial peptides [ 46 , 47 , 48 ].…”

Section: Peptide Drugs Market and Discovery: A Bird’s Eye Viewmentioning

confidence: 99%

Traditional and Computational Screening of Non-Toxic Peptides and Approaches to Improving Selectivity

et al. 2022

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Peptides have positively impacted the pharmaceutical industry as drugs, biomarkers, or diagnostic tools of high therapeutic value. However, only a handful have progressed to the market. Toxicity is one of the main obstacles to translating peptides into clinics. Hemolysis or hemotoxicity, the principal source of toxicity, is a natural or disease-induced event leading to the death of vital red blood cells. Initial screenings for toxicity have been widely evaluated using erythrocytes as the gold standard. More recently, many online databases filled with peptide sequences and their biological meta-data have paved the way toward hemolysis prediction using user-friendly, fast-access machine learning-driven programs. This review details the growing contributions of in silico approaches developed in the last decade for the large-scale prediction of erythrocyte lysis induced by peptides. After an overview of the pharmaceutical landscape of peptide therapeutics, we highlighted the relevance of early hemolysis studies in drug development. We emphasized the computational models and algorithms used to this end in light of historical and recent findings in this promising field. We benchmarked seven predictors using peptides from different data sets, having 7–35 amino acids in length. According to our predictions, the models have scored an accuracy over 50.42% and a minimal Matthew’s correlation coefficient over 0.11. The maximum values for these statistical parameters achieved 100.0% and 1.00, respectively. Finally, strategies for optimizing peptide selectivity were described, as well as prospects for future investigations. The development of in silico predictive approaches to peptide toxicity has just started, but their important contributions clearly demonstrate their potential for peptide science and computer-aided drug design. Methodology refinement and increasing use will motivate the timely and accurate in silico identification of selective, non-toxic peptide therapeutics.

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“…Imiquimod is a TLR7 agonist that enhances the development of the Th1 immune response in macrophages and DCs [124]. Following that, several other synthetic compounds, including the S2 complex (an organic complex of copper chloride, ascorbic acid, and nicotinamide) [125], acetyl salicylic acid [126], and immunomodulatory peptide from cystatin [127], were shown to have both immune modulating and anti-leishmanial properties. Curdlan is a b-(1, 3) glucan with immunomodulatory and pharmacological properties, according to studies [128].…”

Section: Other Drug Candidates Targeting Leishmania Parasitementioning

confidence: 99%

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

Jain¹,

Sahu²,

Kumar³

2022

Preprint

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Leishmaniasis is a tropical disease caused by a protozoan parasite Leishmania that is transmitted via infected female sandflies. At present, leishmaniasis treatment mainly counts on chemotherapy. The currently available drugs against leishmaniasis are costly, toxic, with multiple side effects, and limitations in the administration route. The rapid emergence of drug resistance has severely reduced the potency of anti-leishmanial drugs. As a result, there is a pressing need for the development of novel anti-leishmanial drugs with high potency, low cost, acceptable toxicity, and good pharmacokinetics features. Due to the availability of preclinical data, drug repurposing is a valuable approach for speeding up the development of effective antileishmanial through pointing to new drug targets in less time having low costs and risk. Metabolic pathways of this parasite play a crucial role in the growth and proliferation of Leishmania species during the various stages of their life cycle. Based on available genomics/proteomics information, known pathways-based (sterol biosynthetic pathway, purine salvage pathway, glycolysis, GPI biosynthesis, hypusine, polyamine biosynthesis) Leishmania-specific proteins could be targeted with known drugs that were used in other diseases, resulting in finding new promising anti-leishmanial therapeutics. The present review discusses various metabolic pathways of the Leishmania parasite and some drug candidates targeting these pathways effectively that could be potent drugs against leishmaniasis in the future.

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Peptides to Tackle Leishmaniasis: Current Status and Future Directions

Cited by 20 publications

References 108 publications

Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A2-Derived Peptides

Lessons from a Single Amino Acid Substitution: Anticancer and Antibacterial Properties of Two Phospholipase A2-Derived Peptides

Traditional and Computational Screening of Non-Toxic Peptides and Approaches to Improving Selectivity

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

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