Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle

Favuzza, Paola; Ruiz, Manuel de Lera; Thompson, J. K.; Triglia, Tony; Ngo, Anna; Steel, Ryan; Vavrek, Marissa; Christensen, Janni; Healer, Julie; Boyce, Christopher W.; Guo, Zhuyan; Hu, Mengwei; Khan, Tanweer A.; Murgolo, Nicholas; Zhao, Long; Penington, Jocelyn Sietsma; Reaksudsan, Kitsanapong; Jarman, Kate E.; Dietrich, M.H.; Richardson, Lachlan W; Guo, Kaiyuan; Lopaticki, Sash; Tham, Wai‐Hong; Rottmann, Matthias; Papenfuss, Anthony T.; Robbins, Jonathan A.; Boddey, Justin A; Sleebs, Brad E.; Sabroux, Hélène Jousset; McCauley, John A.; Olsen, David B.; Cowman, Alan F.

doi:10.1016/j.chom.2020.02.005

Cited by 122 publications

(278 citation statements)

References 84 publications

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“…The activity was observed at pH 6.4 (157). RON3, a rhoptry protein inserted into the PVM during or just after invasion, is also thought to be a PM IX substrate from inhibitor studies (158). Rhoptry morphogenesis and attachment defects were observed in the PM IX-depleted strain (156).…”

Section: Key Questionsmentioning

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: Key Questionsmentioning

confidence: 99%

“…The substrates of PM IX responsible for the phenotype are still not known, because RAP1 is not essential (159) and ASP is predicted to be nonessential by a piggy bac transposon mutagenesis screen (160). Maturation of PM IX appears to be autocatalytic (158). PM X is involved in both egress and invasion (156 -158).…”

Section: Key Questionsmentioning

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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“…The recent identification of bioavailable small-molecule compounds which bind to and inhibit the enzymatic activity of PMIX and PMX is promising. 11 The inhibition of PMX reduces the availability of mature PfSUB1 and subsequently PfSUB1-mediated processing of PfSERA5, demonstrating the suitability of such proteases as drug targets blocking erythrocytic egress. The targeting of these proteases that are essential to independent steps within the parasite blood invasion, development and egress stages, has been demonstrated to result in synergistic effects, 49 suggesting the targeting of a combination of these proteases could yield a therapeutic advantage.…”

Section: Discussionmentioning

confidence: 99%

“…7 Serine, cysteine and most recently aspartic protease inhibitors that are capable of arresting merozoite egress have been identified. [8][9][10][11] This process of schizogony during the asexual blood stage is the primary cause for the symptoms associated with the disease, and therefore inhibiting merozoite egress has been proposed as a drug target. 12,13 Cysteine and serine protease and protease-like proteins, some of which accumulate inside the membranebound parasitophorous vacuole (PV) during the late trophozoite and schizont stages, play integral roles in erythrocytic development and in egress 7 ; these include falcipain cysteine proteases, 14 subtilisin serine proteases, 15,16 the upstream plasmepsin aspartic proteases, 17 chiefly plasmepsins IX and X (PMIX and PMX), 10 and the serine repeat antigen (SERA) family of proteins.…”

Section: Introductionmentioning

confidence: 99%

Structure of the Plasmodium falciparum PfSERA5 pseudo‐zymogen

Smith

Clarke

et al. 2020

Protein Science

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PfSERA5, a significantly abundant protein present within the parasitophorous vacuole (PV) and essential for normal growth during the blood-stage life cycle of the malaria parasite Plasmodium falciparum, displays structural similarity to many other cysteine proteases. However, PfSERA5 does not exhibit any detectable protease activity and therefore the role of the PfSERA5 papain-like domain (PfSERA5E), thought to remain bound to its cognate prodomain, remains unknown. In this study, we present a revised structure of the central PfSERA5E domain at a resolution of 1.2 Å, and the first structure of the "zymogen" of this papain-like domain including its cognate prodomain (PfSERA5PE) to 2.2 Å resolution. PfSERA5PE is somewhat structurally similar to that of other known proenzymes, retaining the conserved overall folding and orientation of the prodomain through, and occluding, the archetypal papain-like catalytic triad "active-site" cleft, in the same reverse direction as conventional prodomains. Our findings are congruent with previously identified structures of PfSERA5E and of similar "zymogens" and provide a foundation for further investigation into the function of PfSERA5.

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“…WM382 also cleared P. falciparum in a mouse model of human malaria and prevented transmission to mosquitoes. 16 In the meantime, Dr Duparc remarks, several approaches can help reduce the risk of resistance. "We should select antimalarials that are not resistant to the current drugs and with the minimum of propensity to develop resistance.…”

Section: Tackling Resistancementioning

confidence: 99%