In vitro and in silico studies of naphthoquinones and peptidomimetics toward Plasmodium falciparum plasmepsin V

Sittikul, Pichamon; Songtawee, Napat; Kongkathip, Ngampong; Boonyalai, Nonlawat

doi:10.1016/j.biochi.2018.07.002

Cited by 9 publications

(5 citation statements)

References 62 publications

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“…In addition to uncovering novel parasite biology, these inhibitors have enabled the determination of a high-resolution PM V structure, opening the door to biochemical and pharmacological investigation of this essential enzyme (114). A number of tools have now been turned toward the study of PM V, including inducible Di-Cre excision (115) and post-transcriptional depletion (111,116,117), as well as expression, purification, and activity assessment of PM V expressed from E. coli (110,(118)(119)(120)(121), from insect cells (114), and from parasite culture (109,110). This has enabled rapid progress in our knowledge of this enzyme and its development as a potential antimalarial target.…”

Section: Discoverymentioning

confidence: 99%

“…The PM V flap is several amino acids longer than the analogous region of the digestive vacuole plasmepsins, a difference that could perhaps underlie PM V's unique substrate specificity. Along the flap (but not predicted to contact the substrate) is an unpaired Cys, which has been implicated in PM V's sensitivity to Hg 2ϩ (118,120,121). Connected directly to the flap is an insert made up of two cysteine pairs folded into a cloverleaf-like structure called a "nepenthesin insert," which it shares with Nep1 from the pitcher plant Nepenthesia.…”

Section: Structurementioning

confidence: 99%

See 1 more Smart Citation

Malaria parasite plasmepsins: More than just plain old degradative pepsins

Nasamu¹,

Polino²,

Istvan

et al. 2020

Journal of Biological Chemistry

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Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium. Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion, and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized, whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g. plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous. Some have canonical pepsin-like aspartic protease features, whereas others have unusual attributes, including the nepenthesin loop of plasmepsin V and a histidine in place of a catalytic aspartate in plasmepsin III. We have learned much about the functioning of these enzymes, but more remains to be discovered about their cellular roles and even their mechanisms of action. Their importance in many key aspects of parasite biology makes them intriguing targets for antimalarial chemotherapy. Further consideration of their characteristics suggests that some are more viable drug targets than others. Indeed, inhibitors of invasion and egress offer hope for a desperately needed new drug to combat this nefarious organism.

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Section: Discoverymentioning

confidence: 99%

Section: Structurementioning

confidence: 99%

Malaria parasite plasmepsins: More than just plain old degradative pepsins

Nasamu¹,

Polino²,

Istvan

et al. 2020

Journal of Biological Chemistry

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“…Therefore, given its importance in the parasite’s survival and also relative evolutionary distance from other mammalian aspartyl proteases, Plm V has gained attention as a potential drug target for development of new antimalarials. Though, several naphthoquinone derivatives and PEXEL-based peptidomimetic compounds inhibiting Plm V activity have been identified, yet they require further chemical modifications and research to establish their antimalarial potential as a drug (Sittikul et al, 2018). PEXEL peptidomimetic analogs with either cyclohexylglycine or phenylglycine in the P 2 position have been identified as most potent inhibitors of Plm V till date (Nguyen et al, 2018).…”

Section: Malaria Parasite Plasmepsins: Distinct From Other Aspartyl Pmentioning

confidence: 99%

Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets

Mishra

Singh

2019

Front. Microbiol.

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Malaria, caused by protozoan of genus Plasmodium, remains one of the highest mortality infectious diseases. Malaria parasites have a complex life cycle, easily adapt to their host’s immune system and have evolved with an arsenal of unique proteases which play crucial roles in proliferation and survival within the host cells. Owing to the existing knowledge of enzymatic mechanisms, 3D structures and active sites of proteases, they have been proven to be opportune for target based drug development. Here, we discuss in depth the crucial roles of essential proteases in Plasmodium life cycle and particularly focus on highlighting the atypical “structural signatures” of key parasite proteases which have been exploited for drug development. These features, on one hand aid parasites pathogenicity while on the other hand could be effective in designing targeted and very specific inhibitors for counteracting them. We conclude that Plasmodium proteases are suitable as multistage targets for designing novel drugs with new modes of action to combat malaria.

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“…10,11 In particular, aspartic protease Plms are important targets for developing drugs against malaria. 12–14…”

Section: Introductionmentioning

confidence: 99%

“…10,11 In particular, aspartic protease Plms are important targets for developing drugs against malaria. [12][13][14] Sequencing of the P. falciparum genome has led to the iden-tication of ten different genes that encode the Plms, these enzymes are numbered from I to X. 15 Plms I-IV are located in the acid food vacuole and are active during the intro-erythrocytic stage of the life cycle by providing nutrients for the parasite's growth.…”

Section: Introductionmentioning

confidence: 99%