Although promising candidates are being pursued, these varied strategies have not led to new, clinically effective antimalarial therapies due, in part, to the major effort required for tuning candidate structures toward high selectivity of the small chemical inhibitor for the parasite target ortholog. Labor-intensive, such strategies have also been restricted mechanistically in the biochemical approach to attacking the parasite. Second, classic targeted approaches strive to design selective inhibitors to defined target enzymes. However, subsequent development of lead compounds is hampered by lack of information regarding the identity and binding sites of the cellular target(s), necessary to feed structure-activity relationship chemical optimization strategies and inform potential human homolog cross-reactivity. First, recent high throughput screens based on phenotypic assays against living parasites have been successful in identifying lead compounds that effectively halt parasite proliferation ( 5, 6). Two non-overlapping screening approaches have commonly been used to find new antimalarial candidates. New therapeutic strategies to positively impact malaria disease outcomes are urgently needed. Hence, the number of effective drugs has been whittled down to a handful of compounds over the past decade (reviewed in Refs. 1 and 2), but given that our basic understanding of this infectious organism requires scientific tools that are currently missing, it is not such a surprise that these efforts have not kept pace with growing drug resistance. These measures have had some success in practice (reviewed in Refs. Over the last few years, different strategies and resultant lead compounds to combat this disease have been put forth in the literature. Malaria continues to be a major world health problem, with over one-quarter billion new cases a year worldwide. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5 this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity.

Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are “druggable.” One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. The Plasmodium Kinesin-5 mechanoenzyme is a suitable “next generation” target. Novel antimalarial drugs are urgently needed.

Malaria parasites now show measured resistance to all currently utilized drugs.

Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually.

Igor pro annotation off screen