Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria

Abstract

Severe malariaEven with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death.Sevuparin in phase I studyThe drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated.Sevuparin in phase I/II clinical studyA phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study.Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria.Trial registrationClinicalTrials.gov NCT01442168

Extracellular HMGB1: a therapeutic target in severe pulmonary inflammation including COVID-19?

“…Since heparin treatment includes risks of causing potentially dangerous bleeding one might consider to use low-molecular heparin preparations with very low anticoagulant activity but preserved capacity to bind to HMGB1. One such heparinoid compound has been successfully tested clinically in phase I/II studies of Plasmodium falciparum malaria disease (Leitgeb et al 2017). This molecule also prevented neutrophil-induced lung plasma leakage in a murine sepsis model (Rasmuson et al 2019).…”

Non-Anticoagulant Heparins as Heparanase Inhibitors

“…A nonanticoagulant LMW ROH, Sevuparin (Mw 7.4 kDa), obtained by mild acid hydrolysis of ROH, showed the same activity of UFH both in vitro and in vivo in severe malaria models [139]. Clinical trials are evaluating the adjuvant activity of Sevuparin both in malaria patients and subjects with sickle cell disease, an inherited form of anemia [140,141]. Another LMW ROH, Tafoxiparin (Mw 6.0 kDa) obtained by mild alkaline β-elimination, was found to disrupt rosettes, especially in the majority of fresh blood isolated from children with complicated malaria.…”

Old and Recent Advances in Life Cycle, Pathogenesis, Diagnosis, Prevention, and Treatment of Malaria Including Perspectives in Ethiopia

“…Methylene blue acts by inhibiting falciparum glutathione reductase and as a result, prevents haem polymerization [126]. Polysaccharide heparin analogue Sevuparin (DF02) which is taken as an adjunctive therapy retains the antiadhesive effects of heparin without the antithrombin properties and has been shown to block merozoite invasion, cytoadherence, and rosetting [198]. MMV39048 is an aminopyridine currently in Phase 2a (NCT02880241) trial, and its target was identified to be lipid phosphatidylinositol 4-kinase (PfPI4K).…”