Series 4. vs Gametocytes

[mattodd]

A desirable property of new antimalarials is transmission blocking activity, as is obtained if the compounds are active against the gametocyte stages of the parasite. It was noted previously (#5 ) that we had no data on whether Series 4 was active against gametocytes, so compounds were sent to the Imperial College assay run by Michael Delves and colleagues. A PfATP4 inhibitor should inhibit male gametocyte exflagellation. Four compounds were sent: 2 actives and 2 inactives.

MMV670767
MMV670246
MMV688896
MMV688895

Data were been obtained by email, and are posted here. Apologies for the delay in posting, which is all on me.

In the initial test by Michael, something odd was found. All four compounds were found to be inactive (In the ELN, initial sheet, columns headed "transmission blocking"). Two of the compounds are essentially inactive vs. parasite (>1 uM) so it is not surprising that no transmission blocking effects were seen. The other two (MMV688896 and MMV670767, which are fairly potent against the parasite) would have been expected to show transmission blocking effects as PfATP4 inhibitors.

Michael commented by email that there is usually a general trend that asexual IC50s are more potent than DGFA so it's not completely unexpected that at 1 uM in the DGFA assay the compounds were not active. So he suggested a re-test in dose response up to 25 uM since this should reveal any weak activity.

When this was done (mid-Nov), it looked like the active compounds are indeed weakly active: MMV688896 had a male IC50 of 6.89 uM and MMV670767 looks to be around 12.5 uM but the team didn’t capture the full inhibition curve with the range tested. Both showed a slight activity against female gametocytes. The data are in the ELN entry in the prism file.

Wiki has been updated with these results, as has the S4 paper.

(note also how this adds to the validation that these small differences in structure between these two pairs do indeed translate into different biological activities).

[mattodd]

Linked on wiki, included in Series 4 paper. People who did the work are named as authors on the S4 paper: Jake Baum, Michael J. Delves, Fernando Sánchez-Román Terán, all Imperial. Closing.