Opportunities for Host-targeted Therapies for Malaria

Abstract

Despite the recent successes of artemisinin-based antimalarial drugs, many still die from severe malaria, and eradication efforts are hindered by the limited drugs currently available to target transmissible gametocyte parasites and liver-resident dormant Plasmodium vivax hypnozoites. Host-targeted therapy is a new direction for infectious disease drug development and aims to interfere with host molecules, pathways, or networks that are required for infection or that contribute to disease. Recent advances in our understanding of host pathways involved in parasite development and pathogenic mechanisms in severe malaria could facilitate the development of host-targeted interventions against Plasmodium infection and malaria disease. This review discusses new opportunities for host-targeted therapeutics for malaria and the potential to harness drug polypharmacology to simultaneously target multiple host pathways using a single drug intervention.

New insights into microvascular injury to inform enhanced diagnostics and therapeutics for severe malaria

“…However, de-sequestration interventions would rely on receptor blockade, generally involving the use of recombinant proteins or antibody blockade. These approaches are challenging both in identifying who would benefit, especially early enough in the course of illness, and in how to administer in a low resource-setting, due to their cost and potential storage requirements [19]. We direct the reader to more in-depth reviews looking at cytoadherence adjunctive therapies [2,19].…”

“…For an excellent review on these possibilities please refer to [19]. Recent evidence also supports a role for host-factors not only in contributing to SM, but also supporting the clinical utility of measuring biomarkers of these pathways as accurate community-based prognostic tools to triage children with malaria, as well as, intervention points for adjunctive therapies to attempt to improve clinical outcome [20,21].…”

Anti-tubercular activity of novel 4-anilinoquinolines and 4-anilinoquinazolines

“…The analogous set of methoxy-substituted compounds (4-6) had very similar activity profiles. The 6-OH quinoline (7) showed improved activity relative to the matched quinazoline (1). The inclusion of fluorine substitution on the phenyl ring distal to the quinazoline (8-10) led to markedly increased activity for all three isomers.…”

“…There is growing recognition that pathogen kinases may be targeted in the treatment of infectious diseases. [6][7] Considering the conserved ATP-binding site across species, we looked to screen collections of ATP-competitive inhibitors of human kinases for their anti-tubercular activity.…”

“…Results of alcohol replacement of lapatinib and gefitinib(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).Relative luminescence measured at 3 days after treatment. Values = RLU(sample)/RLU(no compound) at µM concentrations and no effect at 0.625 µM; b IC50 (mean average n=4), 48 h Matched pair comparison of structures similar to erlotinib and lapatinib(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”