A systems biology approach to antimalarial drug discovery

ABSTRACT

Introduction: In spite of significant efforts to reduce malaria deaths, this disease still kills around 445,000 people every year. Overcoming drug resistance is one of the main goals of current malaria research programs. This is challenging, since the biology of Plasmodium is not fully understood, requiring the development of advanced models for data analysis in the search for new antimalarials.

Areas covered: In this review the authors introduce the importance of computational models to address the challenges of drug discovery, presenting examples of pioneering systems biology approaches in the search for new antimalarial drugs and their role in the future of drug research programs. Other related topics are discussed, e.g. regulation of malaria pathogenesis by epigenetics and the importance of new platforms for malaria network.

Expert opinion: The use of a systems biology approach in antimalarial drug discovery emerges in a scenario where the most efficient antimalarial chemotherapies are showing resistance in Southeast Asia. New models for a better understanding of Plasmodium cell function have already proved to be powerful tools for uncovering complex mechanisms of resistance, and have great potential to inform the design of novel small molecules with both high antimalarial activity and transmission-blocking potential to improve the control of malaria.

KEYWORDS:

• Malaria
• systems biology
• resistance
• computational biology
• bioinformatics
• genome

Article highlights

• Malaria remains a worldwide problem, resulting in around 445,000 cases per year, with parasite resistance to the current pipeline of antimalarial drugs being a major challenge for drug discovery.

• Current compounds with antimalarial activity target mostly the intra-erythrocytic stage of the parasite development; novel molecules able to block the human-to-vector transmission are needed as well as safe drugs to replace primaquine aiming to prevent malaria relapses especially by P. vivax.

• A systems biology approach emerges in a scenario where the full understanding of the complex biology of Plasmodium is necessary for successful drug discovery against drug-resistant species.

• Recent identification of molecular targets that are important in different parasite stages has opened up new frontiers for antimalarial drug discovery.

• A combination of genomic data and understanding of the role of epigenetics will help to better describe functions of relevant genes in the complex life cycle of the parasite.

• Worldwide malaria network platforms allowing faster sharing of high quality data are powerful tools not only to accelerate drug discovery but also to quickly overcome the drug resistance mechanisms of the parasite.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors acknowledge funding from the National Council for Scientific and Technological Development (CNPq) and the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) as well as fellowships to A.U. Krettli. The malaria work was undertaken in Fundação Oswaldo Cruz (FIOCRUZ)- MG and the authors acknowledge its support.