Host-parasite immune response is a platform for malaria molecular drug target discovery and development with inclusive systematic review and meta-analysis

Abstract

<title>Abstract</title> <bold>Introduction</bold> : Malaria parasites have antigenic nature which on infecting hosts, elicits immune responses. Here, we deeply review and show that study on these host-parasite immune responses can serve as drivers and platform for discoveries which can further our understanding of disease mechanism and to identify molecular drug targets along points on the haemoglobin (Hb) to haemozoin metabolic degradation path. <bold>Method</bold> : From tentative flowchart for Hb to haemozoin breakdown pathway in malaria parasite which was previously developed by one of authors to this article serving as for-runner, we sought to develop a more elaborate Hb to haemozoin metabolic degradation pathway. This evidence based deep review included systematic review with meta-analysis of previous published works on Hb to haemozoin metabolic degradation and drug targeting in malaria, which included one of core-authors here. This enabled development of a robust chart for Hb to haemozoin degradation by malaria parasite and upgrades the previous tentative flowchart. This particular study is more qualitative than quantitative in design, seeking for proof of drug discovery from Hb degradation pathway engaged by <italic>Plasmodium</italic> parasite. Systematic review of past published works was done by extracting data from two databases of PubMed and Mendeley using PRIMSA guidelines and specific search words related to the title and scope of study. All 21 articles included in the study are selected from experimental studies. Meta-analysis of mined data from both databases engaged the web-based meta-analytical tool Meta-Essentials version xlsx version 1.3 (based on Cochrane principles) for basic Forest plot, Heterogeneity, Sub-group and Moderator analysis, and Publication bias analysis. Microsoft Office Excel 2007 was engaged for further data visualization of features from molecular drug targets, and inhibitors. <bold>Findings and conclusion</bold> : In the systematic review of past literature, data for several approved antimalarial drugs and drug candidate compounds (over 15 in number) acting at points along Hb metabolism, at various stages of development was retrieved, At least 9 of the 21 articles (42.9%) emphasized that beta haematin is a key target for inhibition by the compound inhibitor antimalarial candidate. At least 1 article (4.8%) reported Plasmepsin or Falcipain alongside one other compound in dual target for inhibition. Meta-analysis on data from retrieved articles indicated z-score 1.55 suggestive that the study effect size is consistent with overall meta-analytic estimate. Publication bias analyses filter from Funnel plot and from tests by Failsafe N analyses which engaged Rosenthal, Glesser and Olkin, Orwin and Fisher indicate moderate level of robustness in the findings, relatively low threshold for publication bias. Cautious use of Begg and Mazumdar analysis by ∆xy and its Rank variance, and by Egger’s Regression suggests little to no evidence of publication bias and no evidence of small study effects. Sub-Group data analysis indicated homogenousity that suggests articles from both databases can also be combined to analyze as a unit. The two databases were useful. On visual inspection of Hb metabolic pathway on the newly developed more rigorous chart for Hb breakdown by <italic>Plasmodium</italic> parasite, there are potential drug targets identified along points such as Peroxidative decomposition and Polymerization. Typical list of candidate and approved drug compounds at each of these points along the pathway are shown on the upgraded developed Hb to haemozoin malaria pigment metabolic degradation pathway. Drug discoveries add to the pool of options to treat malaria, which is beneficial and support control effort. There is room to ethically engage evolving biological and biomedical technology, and artificial intelligence to support identification of potently optimized new antimalarials.