Browsing by Author "Gomes, Ana"
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- Bioactive peptides from milk proteins with antioxidant, anti-inflammatory, and antihypertensive activitiesPublication . Borges, Thaís; Coelho, Pedro; Prudêncio, Cristina; Gomes, Ana; Gomes, Paula; Ferraz, Ricardo; Coelho, Pedro; Prudêncio, Cristina; Ferraz, RicardoPeptides from protein ingredients exhibit key biological activities, including antimicrobial, antihypertensive, antioxidant, anti-inflammatory, analgesic, and immunomodulatory effects. Aligning with the One Health approach, there is growing investment in promoting pet health and well-being. As a result, sustainable functional ingredients are increasingly essential for pet food development. In this work, peptides derived from lactoferrins of different mammalian species were synthesized and their antioxidant, anti-inflammatory, and antihypertensive activities were investigated. This study examined the antioxidant, anti-inflammatory, antihypertensive activities, and cytotoxicity of bioactive peptides derived from lactoferrins of various mammalian species through spectroscopical methods. The peptides were produced via chemical synthesis (bottom-up approach). Peptides derived from bovine lactoferrin showed the most promising antioxidant and anti-inflammatory activities, whereas those derived from human lactoferrin showed the highest antihypertensive effects and the lowest cytotoxicity. In short, milk-derived peptides with antioxidant, anti-inflammatory, and antihypertensive activity were identified. This motivates further studies to better characterize these peptides, including their properties and pharmacokinetics in vivo, to assess their true potential as nutraceutical agents.
- Boosting cosmeceutical peptides: coupling imidazolium-based ionic liquids to pentapeptide-4 originates new leads with antimicrobial and collagenesis-inducing activitiesPublication . Gomes, Ana; Bessa, Lucinda J.; Fernandes, Iva; Aguiar, Luísa; Ferraz, Ricardo; Monteiro, Cláudia; Martins, M. Cristina L.; Mateus, Nuno; Gameiro, Paula; Teixeira, Cátia; Gomes, PaulaFollowing our previous reports on dual-action antibacterial and collagenesis-inducing hybrid peptide constructs based on “pentapeptide-4” (PP4, with amino acid sequence KTTKS), whose N-palmitoyl derivative is the well-known cosmeceutical ingredient Matrixyl, herein we disclose novel ionic liquid/PP4 conjugates (IL-KTTKS). These conjugates present potent activity against either antibiotic-susceptible strains or multidrug resistant clinical isolates of both Gram-positive and Gram-negative bacterial species belonging to the so-called “ESKAPE” group of pathogens. Noteworthy, their antibacterial activity is preserved in simulated wound fluid, which anticipates an effective action in the setting of a real wound bed. Moreover, their collagenesis-inducing effects in vitro are comparable to or stronger than those of Matrixyl. Altogether, IL-KTTKS exert a triple antibacterial, antifungal, and collagenesis-inducing action in vitro. These findings provide solid grounds for us to advance IL-KTTKS conjugates as promising leads for future development of topical treatments for complicated skin and soft tissue infections (cSSTI). Further studies are envisaged to incorporate IL-conjugates into suitable nanoformulations, to reduce toxicity and/or improve resistance to proteolytic degradation.
- Chloroquine Analogues as Leads against Pneumocystis Lung PathogensPublication . Gomes, Ana; Ferraz, Ricardo; Ficker, Lauren; Collins, Margaret S.; Prudêncio, Cristina; Cushion, Melanie T.; Teixeira, Cátia; Gomes, PaulaThe impact of Pneumocystis pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, autoimmune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both in vitro and in vivo, we now report the potent action of these compounds on Pneumocystis carinii in vitro Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding.
- “Clicking” an ionic liquid to a potent antimicrobial peptide: on the route towards improved stabilityPublication . Gomes, Ana; Bessa, Lucinda J.; Correia, Patrícia; Fernandes, Iva; Ferraz, Ricardo; Gameiro, Paula; Teixeira, Cátia; Gomes, PaulaA covalent conjugate between an antibacterial ionic liquid and an antimicrobial peptide was produced via “click” chemistry, and found to retain the parent peptide’s activity against multidrug-resistant clinical isolates of Gram-negative bacteria, and antibiofilm action on a resistant clinical isolate of Klebsiella pneumoniae, while exhibiting much improved stability towards tyrosinase-mediated modifications. This unprecedented communication is a prelude for the promise held by ionic liquids -based approaches as tools to improve the action of bioactive peptides.
- Development of a synthetic route towards N4 ,N9 -disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarialPublication . Fonte, Mélanie; Fagundes, Natália; Gomes, Ana; Ferraz, Ricardo; Prudêncio, Cristina; Araújo, Maria João; Gomes, Paula; Teixeira, CátiaMalaria is one of the deadliest infectious diseases in the world and was responsible for 435 000 deaths in 2017, namely by Plasmodium falciparum species.1 Antimalarial drugs are the unique weapon to fight this disease once there is no vaccine yet. Generally antimalarial chemotherapy targets mainly the pathogenic blood stage in humans. However, there is an urgent need of new, economic and safe drugs in order to: (i) block parasite transmission to the vectors, (ii) target parasite forms that, for some species, remain transiently dormant in the liver, and (iii) overcome the resistance against artemisinin-based treatments emerging in some vulnerable population in Africa. Consequently, malaria eradication is only possible with the discovery of new multi-targets drugs.2 Mepacrine (MP, Scheme 1), the first synthetic antimalarial drug, was widely employed but it was rapidly superseded by chloroquine (CQ, Scheme 1), whose efficiency, bioavailability, and safety were far superior. By “dissecting” the chemical structure of QN, the acridine moiety of MP can be seen as the fusion between CQ and the heterocycle core of primaquine (PQ, Scheme 1), another emblematic antimalarial, active against all liver forms of the parasite, and gametocytes. In this context, and based on the fact that one fast and low-cost strategy to accelerate antimalarials development is to recycle classical pharmacophores, the aim of this work is the development a yet unexplored multi-step synthetic route towards 4,9-diaminoacridines (Scheme 1). 2 These can be regarded as respectively corresponding to the fusion between CQ and PQ derivatives. As expected, the preliminary in vitro results showed that the new compounds preserved the activity of the parent drugs, with activity against blood-stage, as in CQ, as well as against all liver forms and gametocytes, similarly to PQ.
- Development of a synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines: On the way to multi-stage antimalarialsPublication . Fonte, Mélanie; Fagundes, Natália; Gomes, Ana; Ferraz, Ricardo; Prudêncio, Cristina; Araújo, Maria João; Gomes, Paula; Teixeira, CátiaA multi-step synthetic route towards N4,N9-disubstituted 4,9-diaminoacridines that, to the best of our knowledge, has no precedence in the literature, has been developed. The target structures are likely to reveal interesting biological activities in the near future, not only due to their mepacrine-like core, but also because they embed simultaneously the pharmacophores of chloroquine and primaquine, antimalarial drugs that act at different stages of malaria infection.
- Disclosure of a promising lead to tackle complicated skin and skin structure infections: antimicrobial and antibiofilm actions of peptide PP4-3.1Publication . Gomes, Ana; Bessa, Lucinda J.; Fernandes, Iva; Ferraz, Ricardo; Monteiro, Cláudia; Martins, M. Cristina L.; Mateus, Nuno; Gameiro, Paula; Teixeira, Cátia; Gomes, PaulaEfficient antibiotics are being exhausted, which compromises the treatment of infections, including complicated skin and skin structure infections (cSSTI) often associated with multidrug resistant (MDR) bacteria, methicillin-resistant S. aureus (MRSA) being the most prevalent. Antimicrobial peptides (AMP) are being increasingly regarded as the new hope for the post-antibiotic era. Thus, future management of cSSTI may include use of peptides that, on the one hand, behave as AMP and, on the other, are able to promote fast and correct skin rebuilding. As such, we combined the well-known cosmeceutical pentapeptide-4 (PP4), devoid of antimicrobial action but possessing collagenesis-boosting properties, with the AMP 3.1, to afford the chimeric peptide PP4-3.1. We further produced its N-methyl imidazole derivative, MeIm-PP4-3.1. Both peptide-based constructs were evaluated in vitro against Gram-negative bacteria, Gram-positive bacteria, and Candida spp. fungi. Additionally, the antibiofilm activity, the toxicity to human keratinocytes, and the activity against S. aureus in simulated wound fluid (SWF) were assessed. The chimeric peptide PP4-3.1 stood out for its potent activity against Gram-positive and Gram-negative bacteria, including against MDR clinical isolates (0.8 ≤ MIC ≤ 5.7 µM), both in planktonic form and in biofilm matrix. The peptide was also active against three clinically relevant species of Candida fungi, with an overall performance superior to that of fluconazole. Altogether, data reveal that PP4-3.1 is as a promising lead for the future development of new topical treatments for severe skin infections.
- Dual-action peptides as potential novel topical agents for treatment of skin and soft tissue infectionsPublication . Gomes, Ana; Bessa, Lucinda; Ferraz, Ricardo; Prudêncio, Cristina; Gameiro, Paula; Teixeira, Cátia; Gomes, PaulaChronic skin and soft-tissue infections (SSTI) such as diabetic foot ulcers (DFU) exhibit signs and symptoms that are consistent with localized bacterial biofilms that contribute to tissue destruction, delayed woundhealing and other serious complications. As such, most current approaches for advanced wound care aim at providing antimicrobial protection to the open wound together with a matrix scaffold (often collagenbased) to boost reestablishment of the skin tissue. While efficient production of recombinant human collagen remains an unmet goal, an alternative sensible option may be the design of formulations containing collagen-boosting instead of collagen-like components. Actually, collagen-boosting peptides, e.g., Matrikines®, are already used in cosmetics to promote extracellular matrix production, rebuilding structure and restoring all functions of healthy skin. Additionally, many antimicrobial peptides (AMP) can also act as wound-healing peptides, thus displaying the dual antimicrobial and tissue-regenerating properties highly desired in novel topical agents for treatment of SSTI. With the increasing prevalence of multi-drug resistant bacteria, and considering the burden that DFU alone represents to human health and healthcare facilities, the development of novel topical agents for effective treatment for this and other severe SSTI is an urgent need.
- Effects of novel triple-stage antimalarial ionic liquids on lipid membrane modelsPublication . Ferraz, Ricardo; Pinheiro, Marina; Gomes, Ana; Teixeira, Cátia; Prudêncio, Cristina; Reis, Salette; Gomes, PaulaPrimaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium-infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria-infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids.
- Enhancement of wound healing in diabetic mice by topical use of a peptide-ionic liquid conjugatePublication . Gomes, Ana; Leal, Ermelindo C.; Ferraz, Ricardo; Calheiros, Daniela; Silva, Jessica da; Gonçalves, Teresa; Teixeira, Inês; Carvalho, Eugénia; Gomes, Paula; Ferraz, RicardoDiabetic foot ulcers (DFU) are one of the most devastating complications of diabetes, with high impact on patient’s quality of life. In worst scenarios, DFU can lead to severe amputation or even death. DFUs are an easy target for microbial pathogens and their effective healing is hampered by the galloping increase of microbial resistance to antibiotics, including from the most prevalent pathogens in DFU, e.g. Staphylococcus aureus. As such, available antibiotics show poor efficacy in the treatment of DFU, leading to a chronic condition that is exacerbated by poor healing rates due to the persistent inflammation, poor oxygenation and low angiogenesis, leading to high risk of ischemia, among other conditions that typically affect patients with diabetes. Our group has recently designed new peptide-based strategies towards the topical treatment of DFU, whereby peptide-ionic liquid conjugates emerged as highly promising agents. One of the best such conjugates, C16-Im-PP4, results from coupling an imidazolium-based ionic liquid with intrinsic antimicrobial activity to the N-terminus of a collagen boosting peptide used in cosmetics, the pentapeptide-4. C16-Im-PP4 showed excellent in vitro properties, namely, wide-spectrum antimicrobial action and collagen-boosting effect on human dermal fibroblasts, prompting the in vivo study here reported. The peptide-ionic liquid conjugate was applied topically on wounds of mice with diabetes. The results show multitargeted actions, at a dose of 1 µg/wound including: i) anti-inflammatory; ii) antioxidant; iii) pro-collagenic; vi) pro-angiogenic; v) antimicrobial; and vi) improved wound maturation effects. Altogether, these results identify this technology as a novel topical treatment for DFU.