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Fulltext Targeting PirAvp and PirBvp Toxins of Vibrio parahaemolyticus with Oilseed Peptides: An In Silico Approach

Ong JH, Wong WL, Wong FC, Chai TT

Antibiotics (Basel), 2021 Oct 05;10(10).
PMID: 34680792 DOI: 10.3390/antibiotics10101211

Acute hepatopancreatic necrosis disease (AHPND), caused by PirAvp- and PirBvp-releasing Vibrio parahaemolyticus strains, has resulted in massive mortality in shrimp aquaculture. Excessive use of antibiotics for AHPND management has led to antibiotic resistance, highlighting the urgency to search for alternatives. Using an in silico approach, we aimed to discover PirAvp/PirBvp-binding peptides from oilseed meals as alternatives to antibiotics. To search for peptides that remain intact in the shrimp digestive tract, and therefore would be available for toxin binding, we focused on peptides released from tryptic hydrolysis of 37 major proteins from seeds of hemp, pumpkin, rape, sesame, and sunflower. This yielded 809 peptides. Further screening led to 24 peptides predicted as being non-toxic to shrimp, fish, and humans, with thermal stability and low water solubility. Molecular docking on the 24 peptides revealed six dual-target peptides capable of binding to key regions responsible for complex formation on both PirAvp and PirBvp. The peptides (ISYVVQGMGISGR, LTFVVHGHALMGK, QSLGVPPQLGNACNLDNLDVLQPTETIK, ISTINSQTLPILSQLR, PQFLVGASSILR, and VQVVNHMGQK) are 1139-2977 Da in mass and 10-28 residues in length. Such peptides are potential candidates for the future development of peptide-based anti-AHPND agents which potentially mitigate V. parahaemolyticus pathogenesis by intercepting PirAvp/PirBvp complex formation.
Fulltext In Silico Identification of Multi-target Anti-SARS-CoV-2 Peptides from Quinoa Seed Proteins

Wong FC, Ong JH, Kumar DT, Chai TT

Int J Pept Res Ther, 2021;27(3):1837-1847.
PMID: 33867899 DOI: 10.1007/s10989-021-10214-y

Peptides are promising antagonists against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). To expedite drug discovery, a computational approach is widely employed for the initial screening of anti-SARS-CoV-2 candidates. This study aimed to investigate the potential of peptides from quinoa seed proteins as multi-target antagonists against SARS-CoV-2 spike glycoprotein receptor-binding domain, main protease, and papain-like protease. Five quinoa proteins were hydrolyzed in silico by papain and subtilisin. Among the 1465 peptides generated, seven could interact stably with the key binding residues and catalytic residues of the viral targets, mainly via hydrogen bonds and hydrophobic interactions. The seven peptides were comparable or superior to previously reported anti-SARS-CoV-2 peptides based on docking scores. Key residues in the seven peptides contributing to binding to viral targets were determined by computational alanine scanning. The seven peptides were predicted in silico to be non-toxic and non-allergenic. The peptides ranged between 546.66 and 3974.87 g/mol in molecular mass, besides exhibiting basic and cationic properties (isoelectric points: 8.26-12.10; net charges: 0.1-4.0). Among the seven peptides, VEDKGMMHQQRMMEKAMNIPRMCGTMQRKCRMS was found to bind the largest number of key residues on the targets. In conclusion, seven putative non-toxic, non-allergenic, multi-target anti-SARS-CoV-2 peptides were identified from quinoa seed proteins. The in vitro and in vivo efficacies of the seven peptides against SARS-CoV-2 deserve attention in future bench-top testing.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10989-021-10214-y.
Fulltext Purification, Identification and Characterization of Antioxidant Peptides from Corn Silk Tryptic Hydrolysate: An Integrated In Vitro-In Silico Approach

Ong JH, Koh JA, Cao H, Tan SA, Abd Manan F, Wong FC, et al.

Antioxidants (Basel), 2021 Nov 17;10(11).
PMID: 34829693 DOI: 10.3390/antiox10111822

Corn silk (CS) is an agro-by-product from corn cultivation. It is used in folk medicines in some countries, besides being commercialized as health-promoting supplements and beverages. Unlike CS-derived natural products, their bioactive peptides, particularly antioxidant peptides, are understudied. This study aimed to purify, identify and characterize antioxidant peptides from trypsin-hydrolyzed CS proteins. Purification was accomplished by membrane ultrafiltration, gel filtration chromatography, and strong-cation-exchange solid-phase extraction, guided by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt radical cation (ABTS•+) scavenging, hydrogen peroxide scavenging, and lipid peroxidation inhibition assays. De novo sequencing identified 29 peptides (6-14 residues; 633-1518 Da). The peptides consisted of 33-86% hydrophobic and 10-67% basic residues. Molecular docking found MCFHHHFHK, VHFNKGKKR, and PVVWAAKR having the strongest affinity (-4.7 to -4.8 kcal/mol) to ABTS•+, via hydrogen bonds and hydrophobic interactions. Potential cellular mechanisms of the peptides were supported by their interactions with modulators of intracellular oxidant status: Kelch-like ECH-associated protein 1, myeloperoxidase, and xanthine oxidase. NDGPSR (Asn-Asp-Gly-Pro-Ser-Arg), the most promising peptide, showed stable binding to all three cellular targets, besides exhibiting low toxicity, low allergenicity, and cell-penetrating potential. Overall, CS peptides have potential application as natural antioxidant additives and functional food ingredients.
Fulltext Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants

Foong SC, Tan ML, Foong WC, Marasco LA, Ho JJ, Ong JH

Cochrane Database Syst Rev, 2020 May 18;5(5):CD011505.
PMID: 32421208 DOI: 10.1002/14651858.CD011505.pub2

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use.
OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs.
SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019).
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification.
MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome.
AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.