Macintyre et al. Malar J (2018) 17:402 https://doi.org/10.1186/s12936-018-2549-1 Malaria Journal REVIEW Open Access Injectable anti‑malarials revisited: discovery and development of new agents to protect against malaria Fiona Macintyre1, Hanu Ramachandruni1, Jeremy N. Burrows1, René Holm2,3, Anna Thomas1, Jörg J. Möhrle1, Stephan Duparc1, Rob Hooft van Huijsduijnen1 , Brian Greenwood4, Winston E. Gutteridge1, Timothy N. C. Wells1* and Wiweka Kaszubska1 Abstract Over the last 15 years, the majority of malaria drug discovery and development eforts have focused on new mol- ecules and regimens to treat patients with uncomplicated or severe disease. In addition, a number of new molecular scafolds have been discovered which block the replication of the parasite in the liver, ofering the possibility of new tools for oral prophylaxis or chemoprotection, potentially with once-weekly dosing. However, an intervention which requires less frequent administration than this would be a key tool for the control and elimination of malaria. Recent progress in HIV drug discovery has shown that small molecules can be formulated for injections as native molecules or pro-drugs which provide protection for at least 2 months. Advances in antibody engineering ofer an alternative approach whereby a single injection could potentially provide protection for several months. Building on earlier profles for uncomplicated and severe malaria, a target product profle is proposed here for an injectable medicine providing long-term protection from this disease. As with all of such profles, factors such as efcacy, cost, safety and tolerability are key, but with the changing disease landscape in Africa, new clinical and regulatory approaches are required to develop prophylactic/chemoprotective medicines. An overall framework for these approaches is sug- gested here. Keywords: Malaria, Plasmodium, Chemoprotection, Prophylaxis, Liver schizont, Intra-muscular, Target candidate profle, Target product profle Introduction way to new approaches against this disease. In addition, One of the challenges of malaria control is to be able recent developments in monoclonal antibody technology to provide protection for vulnerable populations. In may be applicable to protect against malaria, especially recent years, there has been great progress in the use of in vulnerable populations. Tis paper discusses how drug regimens to prevent infections in children. How- such treatments would ft the target product profles for ever, these require frequent drug administration. One malaria, and a regulatory pathway for their development. alternative that has been tested is the use of long-acting Since they pose similar challenges and possibilities from injectable formulations. Although there are currently this perspective, the discussion of small molecules and no long-acting injectable medicines in development for antibodies was combined. malaria, new formulation technologies, similar to those developed for prophylaxis against HIV, might point the Background Over the last decade, there has been a consider- able increase in the portfolio of new molecules which *Correspondence: [email protected] 1 Medicines for Malaria Venture, Route de Pré Bois 20, 1215 Geneva, are being developed for the treatment of malaria [1, Switzerland 2]. New paradigms of screening [3–8] have led to Full list of author information is available at the end of the article another generation of molecules progressing to clinical © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Macintyre et al. Malar J (2018) 17:402 Page 2 of 18 development, aimed at producing new medicines which highly efective vaccination regimen for malaria remains overcome the current problems of multi-drug resist- very high. ant malaria [9–11] and which also simplify therapy Identifying new classes of anti-malarial chemoprotec- from the current 3-day therapy, to single exposure tive molecules targeting either blood- or liver-stage has cures. Protecting vulnerable populations from clinically historically been limited by the lack of known molecu- signifcant infections is also a key aspect of malaria lar targets and of high-throughput screening methods. control and elimination [12]. Although a highly efec- However, in the last 10 years there has been a dramatic tive vaccine is the ultimate goal of much basic malaria increase in the deployment of high density, phenotypic, research, the absence of a sterilizing immune response cell-based high-throughput screens of Plasmodium blood to naturally acquired disease shows how difcult such stages [24] and new chemotypes, which are active against a target is likely to be [13]; current candidate vaccines the blood stages of Plasmodium infection, have been provide a protective efcacy in the range of 30–50% identifed [25]. Tese families of molecules can then be [14]. tested for activity against other stages of the parasite life Malaria chemoprophylaxis can be achieved by a vari- cycle including hepatic schizonts. Examples in the Medi- ety of diferent mechanisms. Causal prophylactics tar- cines for Malaria Venture (MMV) pipeline of compounds get the asexual hepatic stages of malaria. Atovaquone (a having both blood and liver stage activity [1] include: Plasmodium mitochondrial bc1 inhibitor binding to the the DHODH (dihydroorotate dehydrogenase) inhibi- Q0 site of the complex), pyrimethamine and cycloguanil tor DSM265 [26, 27], the PI-4 kinase inhibitor MMV048 and its prodrug proguanil (selective inhibitors of dihy- (MMV390048; [28]) and the EF2 (Elongation Factor 2) drofolate reductase, DHFR), sulfadoxine (an inhibitor of inhibitor DDD498 (DDD107498; [29]), now also known Plasmodium dihydropteroate synthase, DHPS) and the as M5717. Tese molecules have helped identify new 8-aminoquinolines primaquine and tafenoquine are the molecular targets in liver schizonts. Other scafolds such only causal prophylactics with proven clinical efcacy. In as KAF156 [30] have good activity against hepatic schiz- suppressive chemoprophylaxis, the parasite is killed once onts. However, although the main mechanism of resist- it enters the erythrocytic stages of the lifecycle, stop- ance generation involves PfCARL, KAF156’s molecular ping the infection at a low level of parasitaemia before site of action is still to be elucidated [31]. More recently, it becomes clinically signifcant. Inhibitors of beta-hae- high-throughput screens of the hepatic schizont stages matin formation, such as chloroquine and mefoquine, have been carried out for murine parasites [32], increas- and (plastid) ribosomal inhibitors, such as doxycycline, ing the possibility of the identifcation of compounds are suppressive chemoprophylactics, and must be given which are selectively active against hepatic schizonts. for at least 2 weeks after leaving a malaria-endemic area Te immediate challenge is to develop high-throughput to clear any parasites that emerge from the liver after a hepatic schizont stage assays using sporozoites from person has left the endemic area. Currently, the pre- Plasmodium falciparum, and progress in this direction dominant oral prophylactics used by travelers are (rarely) is being made. Tis is particularly important in order to mefoquine, doxycycline and atovaquone–proguanil. confrm activity of compounds without asexual blood Tese were initially developed as treatments for uncom- stage activity, and to avoid a focus on murine-malaria plicated malaria [15, 16]. Tey were subsequently shown specifc prophylaxis. to have good protective efcacy when delivered at lower Work on injectable depot anti-malarials was a key part doses on a weekly basis, in the case of mefoquine, and a of the previous malaria eradication campaign with the daily basis in the case of atovaquone–proguanil, respec- development of 4-4′-diacetylaminosulphone (DADDS), tively [17, 18]. a long-acting prodrug of the DHPS inhibitor dapsone, Protective vaccine strategies have focused on develop- and cycloguanil pamoate (CI-501; [33, 34]). Clinical pro- ing an immune response which blocks the initial infec- tection over 3–5 months was achieved in the published tion, using the parasite antigen CSP-1 (circumsporozoite clinical trial, but the dose had to be delivered deep into protein; [19]). Although a high level of protection has the gluteal muscle tissues (350 mg in adults) and caused not currently been achieved with such vaccine candi- local discomfort and abscesses [35]. Failure to protect date approaches, they have provided a proof of concept was assumed to be due to cross resistance with pyrimeth- that antibodies can be generated that prevent the initial amine, which was emerging at the time. Interest in long- infection of the hepatocyte by sporozoites [20–23]. Ef- lasting anti-malarials was renewed in 1976, supported cacious vaccines would hold tremendous promise for by the UNDP/World Bank/WHO special program for prophylaxis, but unlike many viral infections, malaria is Research and Training in Tropical Disease [WHO CHE- not a disease