Tuesday, December 09, 2014

One more add-on to brand of New Generation Antimalarials


I have previously blogged a few posts on efforts to fight malaria. Malaria has been a longstanding problem in tropics and efforts to control have achieved reasonable success, at least in some parts of the world. As recently noted, there is a growing need for better Anti-malarials (Link). More recently there is a headlines circulating over the web- "A new antimalarial compound". And this post is all about it.

Table 1: Drugs in development through MMV 
The original publication is based on a paper published in nature, in 2010. By using a high throughput phenotypic assay (The screening was done by identifying molecules that block the proliferation of Plasmodium falciparum strain 3D7 in co-cultures with human erythrocytes), 309474 unique compounds. The screen generated 1,134 valid hits. Of them 172 chemicals was closely evaluated. The database is available at St.Jude research. In nutshell, reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. One among the 3 series of potential chemicals was DHIQs (dihydroisoquinolones). (+)-SJ733 is a component of that class. There is a huge list of chemicals that are gaining popularity for use against plasmodium which are developed in partnership with MMV (Medicines for Malaria Venture). A list of some well known compounds is shown in Table 1.

Table 2: SJ733 
pfATP4 is a P-type cation-ATPase which serve as parasite plasma membrane protein with sequence similarities to Na+-ATPases. It is the target for many types of antimalarials such as Pyrazoleamide compounds, Spiroindolone etc. It counters the influx of Na+, thereby maintaining a low Na+ content. SJ733 or (+)-SJ557733 (both are same chemical), disrupts this action which leads changes in physical structure of RBC. The RBC is more shrunken, resembling a pattern of eryptosis. The RBC is seen as a damaged version in the reticuloendothelial system. The next step is obvious, immune system attacks the RBC thereby defeating the plasmodium inside. This is something similar to people who have G6PD deficiency. Plasmodium simply doesn't survive well cause of similar RBC elimination.

In a mouse model, the drug was administered as a single dose which cleared about 80 percent of malaria parasites within 24 hours. After 48 hours the parasite was not detectable. And here is the most interesting part. This target molecule is a heavily conserved system and mutation has a huge fitness cost. That means resistance can develop but in low level. To quote from Kiplin Guy (Source), "Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose. These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude".

Oh of course, Clinical trials are now on the next "To Do" list.

Jiménez-Díaz M.B., Ebert D., Salinas Y., Pradhan A., Lehane A.M., Myrand-Lapierre M.E., O'Loughlin K.G., Shackleford D.M., Justino de Almeida M. & Carrillo A.K. & (2014). (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.PNAS PMID: 25453091

Guiguemde WA, Shelat AA, Bouck D, Duffy S, Crowther GJ, Davis PH, Smithson DC, Connelly M, Clark J, Zhu F, Jiménez-Díaz MB, Martinez MS, Wilson EB,Tripathi AK, Gut J, Sharlow ER, Bathurst I, El Mazouni F, Fowble JW, Forquer I, McGinley PL, Castro S, Angulo-Barturen I, Ferrer S, Rosenthal PJ, Derisi JL,Sullivan DJ, Lazo JS, Roos DS, Riscoe MK, Phillips MA, Rathod PK, Van Voorhis WC, Avery VM, Guy RK. Chemical genetics of Plasmodium falciparum. Nature. 2010 May 20;465(7296):311-5. PMID: 20485428