Anti-plasmodial and anti-inflammatory activities of cyclotide-rich extract and fraction of &lt;i&gt;Oldenlandia affinis&lt;/i&gt; (R. &amp; S.) D.C. (&lt;i&gt;Rubiaceae&lt;/i&gt;)

Nworu, Chukwuemeka S.; Ejikeme, Tochukwu Ifenyinwa; Ezike, Adaobi Chioma; Ndu, Okechukwu; Akunne, Theophine Chinwuba; Onyeto, Collins Azubuike; Okpalanduka, Paul; Akah, Peter A.

doi:10.4314/ahs.v17i3.26

Cited by 14 publications

(11 citation statements)

References 57 publications

(50 reference statements)

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“…Plants from the seemingly unrelated Cucurbitaceae, Fabaceae, Rubiaceae, Solanaceae, and Violaceae families produce antimicrobial and insecticidal “mini-proteins,” known as cyclotides ( 97 ), which represent the best-known plant antimicrobial peptides and display activity against multiple groups of pathogens. Antimalarial activity has been reported from cyclotide-rich extracts of Oldenlandia affinis (Rubiaceae), a West African medicinal plant ( 98 ). Various cyclotides from the sweet violet ( Viola odorata ) demonstrated broad-spectrum antibacterial and antifungal activities, with low inhibitory concentrations against E. coli , Klebsiella pneumoniae , Pseudomonas aeruginosa , Salmonella enterica , S. aureus, and the fungi Candida albicans ( 99 , 100 ), Fusarium graminearum ( 101 ), and Fusarium oxysporum ( 102 ).…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Parthasarathy

Borrego

Savka

et al. 2021

Journal of Biological Chemistry

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For millennia, humanity has relied on plants for its medicines, and modern pharmacology continues to reexamine and mine plant metabolites for novel compounds and to guide improvements in biological activity, bioavailability, and chemical stability. The critical problem of antibiotic resistance and increasing exposure to viral and parasitic diseases has spurred renewed interest into drug treatments for infectious diseases. In this context, an urgent revival of natural product discovery is globally underway with special attention directed toward the numerous and chemically diverse plant defensive compounds such as phytoalexins and phytoanticipins that combat herbivores, microbial pathogens, or competing plants. Moreover, advancements in “ omics ,” chemistry, and heterologous expression systems have facilitated the purification and characterization of plant metabolites and the identification of possible therapeutic targets. In this review, we describe several important amino acid–derived classes of plant defensive compounds, including antimicrobial peptides ( e.g. , defensins, thionins, and knottins), alkaloids, nonproteogenic amino acids, and phenylpropanoids as potential drug leads, examining their mechanisms of action, therapeutic targets, and structure–function relationships. Given their potent antibacterial, antifungal, antiparasitic, and antiviral properties, which can be superior to existing drugs, phytoalexins and phytoanticipins are an excellent resource to facilitate the rational design and development of antimicrobial drugs.

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Section: Antimicrobial Peptidesmentioning

confidence: 99%

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Parthasarathy

Borrego

Savka

et al. 2021

Journal of Biological Chemistry

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“…Cyclotides are a family of plant-derived peptides featuring a cyclic backbone cross-braced by a cystine knot in which a trio of disulfide bonds link through one another to stabilize the peptide core (Craik et al, 1999). The traditional uterotonic medicine 'kalata-kalata' from which cyclotides were first identified (Craik et al, 1999) is prepared by boiling the leaves of the African herb Oldenlandia affinis, and so reports of its oral bioactivity in ethnomedicinal settings suggest oral and heat stability of the active ingredients (Gran, 1970;Nworu et al, 2017). Subsequent studies on cyclotides isolated from O. affinis have shown them to be impervious to degradation by enzymes in vitro, high temperatures, or low pH environments (Colgrave and Craik, 2004).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold

Huang

Poth

et al. 2019

International Journal of Pharmaceutics

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Oral activity has been described for cyclotide-containing traditional medicines, and demonstrated for reengineered cyclotides bearing grafted therapeutic epitopes, highlighting their potential for translation to the clinic. Here we report preclinical pharmacokinetic parameters for the prototypic cyclotide kalata B1 (kB1) and two orally active grafted analogues, ckb-KAL and ckb-KIN, to provide the first in vivo dose-exposure metrics for cyclotides. Native and grafted kB1 molecules exhibited multiple compartment kinetics and measurable but limited oral bioavailability of similar magnitude to several orally administered peptide drugs in the clinic. Cyclotides are mostly associated with the central compartment, and display small (0.07-0.1 L kg-1 for kB1 and ckb-KIN) to moderate (1 L kg-1 for ckb-KAL) steady state volumes of distribution. This study provides new data essential to the evaluation of cyclotides as therapeutics, validating them as a viable drug design scaffold with tunable pharmacokinetic properties.

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“…In addition, it was also able to decrease the content of p24 in the HIV viral particle, disrupting the structural integrity of the virus. These effects could help the efficacy of classical retroviral therapeutic agents, although it has not been investigated yet [112].…”

Section: Biological Activities Of Naturally-occurring Cyclotidesmentioning

confidence: 99%

“…Other cyclotides isolated from O. affinis have also anti-plasmodial activity against Plasmodium berghei as well as anti-inflammatory activity by decreasing the expression levels of pro-inflammatory mediators such as iNO and TNF-α [112].…”

Section: Biological Activities Of Naturally-occurring Cyclotidesmentioning

confidence: 99%

The Potential of the Cyclotide Scaffold for Drug Development

Camarero

Campbell

2019

Biomedicines

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Cyclotides are a novel class of micro-proteins (≈30–40 residues long) with a unique topology containing a head-to-tail cyclized backbone structure further stabilized by three disulfide bonds that form a cystine knot. This unique molecular framework makes them exceptionally stable to physical, chemical, and biological degradation compared to linear peptides of similar size. The cyclotides are also highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, and are orally bioavailable and able to cross cellular membranes to modulate intracellular protein–protein interactions (PPIs), both in vitro and in vivo. These unique properties make them ideal scaffolds for many biotechnological applications, including drug discovery. This review provides an overview of the properties of cyclotides and their potential for the development of novel peptide-based therapeutics. The selective disruption of PPIs still remains a very challenging task, as the interacting surfaces are relatively large and flat. The use of the cell-permeable highly constrained polypeptide molecular frameworks, such as the cyclotide scaffold, has shown great promise, as it provides unique pharmacological properties. The use of molecular techniques, such as epitope grafting, and molecular evolution have shown to be highly effective for the selection of bioactive cyclotides. However, despite successes in employing cyclotides to target PPIs, some of the challenges to move them into the clinic still remain.

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Anti-plasmodial and anti-inflammatory activities of cyclotide-rich extract and fraction of <i>Oldenlandia affinis</i> (R. & S.) D.C. (<i>Rubiaceae</i>)

Cited by 14 publications

References 57 publications

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Amino acid–derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development

Pharmacokinetic characterization of kalata B1 and related therapeutics built on the cyclotide scaffold

The Potential of the Cyclotide Scaffold for Drug Development

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