Crucial residues in falcipains that mediate hemoglobin hydrolysis

Pasupureddy, Rahul; Verma, Sonia; Pant, A.K.; Sharma, Ruby; Seshadri, Sriram; Pande, Veena; Saxena, Ajay K.; Dixit, Rajnikant; Pandey, Kailash C.

doi:10.1016/j.exppara.2019.01.005

Cited by 7 publications

(5 citation statements)

References 44 publications

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“…Previous studies have linked plant and animal-derived enzymes (proteases) and phytochemicals of plant origin, especially phenolics, terpenoids, and organonitrades, to protein precipitating ability. Falcipain, a proteolytic enzyme produced by the Plasmodium falciparum parasite, is associated with the hydrolysis of hemoglobin into amino acids for reuse in protein synthesis [ 26 ]. Proteolytic enzymes isolated from the Vallesia glabra plant hydrolyze peptide bonds of hemoglobin to release polypeptides and amino acids [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Hemoglobin Precipitation: An Index of In Vitro Vasoconstrictive Activities of Methanol Leaf Extracts of Croton megalocarpus Hutch and Lantana camara Linn

Muindi

Kibiti

Ngugi

2021

Evidence-Based Complementary and Alternative Medicine

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The function of innate hemostasis aids the body in bleeding control, preventing the loss of excessive amounts of blood following low-degree injuries. However, injuries of a higher degree may require extrinsic intervention to stop life-threatening blood loss. Astringent agents’ actions result in mechanical constriction of small blood vessels and shrinkage of body tissues, thereby stopping blood loss. This enhances the primary phase of hemostasis, where vasoconstriction is the main mechanism at play during the initial response to injury. The effects of plant extracts on protein precipitation have been linked to blood vessel vasoconstriction. Traditionally, the leaves of Croton megalocarpus Hutch and Lantana camara Linn plants are used by communities living in Makueni County, Kenya, for peripheral bleeding control. However, the effects of extracts of both plants on hemoglobin precipitation have not been evaluated scientifically. In the current study, the activities of methanol extracts of C. megalocarpus (H.) and L. camara (L.) on blood protein precipitation were investigated. The leaves were harvested, cleaned, air-dried, milled, and extracted in absolute methanol before being concentrated into dry powders. A qualitative phytochemical screen revealed the presence of terpenoids, steroids, tannins, phenols, flavonoids, reducing sugars, cardiac glycosides, and carbohydrates in the methanol extract of C. megalocarpus (H.). The methanol extracts of L. camara (L.) contained cardiac glycosides, saponins, tannins, phenols, terpenoids, reducing sugars, and carbohydrates. The hemoglobin precipitation ability of various concentrations of extracts using mice samples was presented as relative astringency following the tannic acid external standard method. Methanol extracts C. megalocarpus (H.) and L. camara (L.) had significantly higher relative astringency compared with the normal control, indicating a protein precipitating activity. The relative astringency observed in both plant extracts is linked to the activity of tannins, phenols, flavonoids, and saponins detected during preliminary phytochemical screening.

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Section: Discussionmentioning

confidence: 99%

Hemoglobin Precipitation: An Index of In Vitro Vasoconstrictive Activities of Methanol Leaf Extracts of Croton megalocarpus Hutch and Lantana camara Linn

Muindi

Kibiti

Ngugi

2021

Evidence-Based Complementary and Alternative Medicine

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“…Interestingly, this substrate binding motif is separate from the catalytic triad of FP‐2 and specifically regulates hemoglobin hydrolysis. Recently, crucial residues that mediate the interaction between falcipain‐2 and hemoglobin were identified, highlighting the importance of this PPI in hemoglobin hydrolysis . Future development of mimics of the FP‐2 “arm” via constrained peptides or peptidomimetics may serve as an effective strategy to disrupt its interaction with hemoglobin as an alternative approach for FP‐2 inhibition.…”

Section: Peptidomimetics Targeting Falcipain‐2mentioning

confidence: 99%

TargetingPlasmodiumwith constrained peptides and peptidomimetics

Helton

Kennedy

2020

IUBMB Life

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Malaria remains a worldwide health concern with an estimated quarter of a billion people infected and nearly half a million deaths annually. Malaria is caused by a parasite infection from Plasmodium strains which are transmitted from mosquitoes into the human host. Although several small molecule inhibitors have been found to target the early stages of transmission and prevent parasite proliferation, multiple drug resistant parasite strains have emerged and drug resistance remains a major hurdle. As an alternative to small molecule inhibition, several peptide-based therapeutics have been explored for their potential as antimalarial compounds. Chemically constrained peptides or peptidomimetics were developed to target large binding interfaces of parasite-based proteins that have historically been difficult to selectively inhibit using small molecules. Here, we review ongoing research aimed at developing constrained peptides targeting protein-protein interactions pertinent to malaria pathogenesis. These targets include Falcipain-2, the J domain of CDPK1, myosin A tail domain interacting protein, the PKA signaling pathway, and an unclear signaling pathway involving angiotensin-derived peptides. Diverse synthetic methods were also used for each target. Merging parasite biology with synthetic strategies may provide new opportunities to develop alternative methods for uncovering novel antimalarials and may offer an alternate source for targeting drug-resistant parasite strains.

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“…Molecular docking results indicated both the residues interacted with Hb-α as well as Hb-β subunits with interactions mediated primarily through this position (Figure 2). A specific inhibitor which could target this position could have potential applications in arresting the parasite hemoglobin degradome [20].…”

Section: Hemoglobin Hydrolysismentioning

confidence: 99%

“…Hemoglobin degradation as a source for parasite growth was also shown to be dependent on the hemoglobin tetramer composition. Children (<5 years) have different Hb subunits (HbF, α 2 γ 2 ) as compared to adults (HbA, α 2 β 2 ), and malaria mortality rates have consistently indicated child mortality to be higher (61% of [20]. The essential amino acid isoleucine (I) was found to be a main differentiating factor as it is absent in both α and β chains but present in γ subunit and makes up to 99% of encoded proteins in P. falciparum proteome [21].…”

Section: Hemoglobin Hydrolysismentioning

confidence: 99%

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Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

Pasupureddy¹,

Seshadri²,

Dixit³

et al. 2020

Parasitology and Microbiology Research

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Malaria is one of the most deadly diseases infecting humans. Advances in elimination and vector control have reduced the global malaria burden in the past decade; however, the emerging threat of drug resistance and suboptimal vaccine efficacies threaten global eradication efforts. Unlocking novel drug and vaccine targets while simultaneously mitigating spread of resistant strains seems to be the need of the hour. Protein-protein interactions (PPIs), an integral part of hostpathogen cross-talk and parasite survival, have only recently emerged as promising drug targets. Large PPI networks (interactome) are being developed to better our understanding of various parasite biochemical pathways. In this chapter, we throw light on several newly characterized protein-protein interactions between the host (humans) and parasite (plasmodium) in key processes such as hemoglobin degradation, enzyme regulation, protein export, egress, invasion, and drug resistance and further discuss their viability for development as novel chemotherapeutic targets.

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Crucial residues in falcipains that mediate hemoglobin hydrolysis

Cited by 7 publications

References 44 publications

Hemoglobin Precipitation: An Index of In Vitro Vasoconstrictive Activities of Methanol Leaf Extracts of Croton megalocarpus Hutch and Lantana camara Linn

Hemoglobin Precipitation: An Index of In Vitro Vasoconstrictive Activities of Methanol Leaf Extracts of Croton megalocarpus Hutch and Lantana camara Linn

TargetingPlasmodiumwith constrained peptides and peptidomimetics

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

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