Low-Throughput Screening Identifies Potent Antimalarial Candidate MMV688533 with Single-Dose Cure Potential

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This issue of *Science Translational Medicine* features a study on the discovery of a novel antimalarial drug candidate by scientists from Sanofi in collaboration with several universities. Diverging from the mainstream approach of high-throughput screening millions of compounds, the authors assembled a screening library comprising 350 compounds already in clinical development at Sanofi, plus 450 compounds exhibiting activity against homologous proteins of various *Plasmodium* targets in other species. Screening these 800 compounds via a cell-based assay yielded 6 chemical series and 120 hit compounds with potency better than 1 μM, achieving a 15% hit rate—significantly higher than the ~0.5% typical of high-throughput screening. The authors detail the optimization of one series, wherein straightforward chemical modifications yielded the nanomolar-potency candidate drug MMV688533. This compound not only exhibits a broad antimalarial spectrum and rapid onset of action, but also demonstrates durable efficacy; a single oral dose cured the infection in a humanized mouse model, with a relatively slow rate of resistance development. Phase I clinical trials for this compound have already commenced in Australia.

Drug Source Analysis

The COVID-19 pandemic last year underscored the severe threat posed by infectious diseases. Indeed, infectious diseases have historically been a primary menace to human health, and the modern pharmaceutical industry itself originated from the development of anti-infective agents. While infectious diseases have been largely controlled in developed nations, a substantial portion of the global population remains vulnerable to various infectious threats. These so-called neglected diseases (distinct from rare diseases, as they are highly prevalent but lack dedicated pharmaceutical R&D investment) constitute major health challenges in low-income countries. In 2019, an estimated 2.29 million malaria cases occurred globally, resulting in 400,000 deaths. Approximately a decade ago, the pharmaceutical sector launched a collaborative drug development initiative targeting neglected tropical diseases, with many retired industry scientists volunteering their expertise. Major pharmaceutical companies have also provided support, including supplying compounds for screening and conducting routine assays (e.g., stability testing).

New drug discovery typically begins with high-throughput screening (HTS). However, if a screening library lacks suitable molecular scaffolds, merely increasing the number of compounds will not improve the probability of discovering lead compounds. The screening strategy employed in this work is rather ingenious. That said, it is also possible that Sanofi does not prioritize antimalarial drug development as a core focus, thereby compelling the authors to adopt this approach. Biological processes are highly complex; the very fact that any system functions is an almost unfathomable miracle. Higher organisms are essentially "me-better" iterations of lower ones, with many proteins sharing conserved functions. Consequently, compounds active against human proteins have a relatively high likelihood of exhibiting activity against *Plasmodium* proteins, provided these targets are not exclusive to humans. Identifying 120 highly active compounds from a pool of 800 indeed represents a remarkably high hit rate. This reminds me of a notorious bank robber who, when asked why he robbed banks, replied, "Because that's where the money is."

The remaining half of the compounds are sourced from high-quality clinical-stage candidates. Although *Plasmodium* (the malaria parasite) may not be their intended therapeutic target, these are all highly optimized molecules. Beyond exhibiting exceptional potency against their primary targets, numerous drug-like properties—including chemical stability, metabolic stability, tissue distribution, and off-target activity—have already been systematically optimized. As the adage goes, "one takes on the hue of one's surroundings." Once such a pre-optimized compound hits your screening target, the difficulty of developing it into a drug is substantially lower than that of a random screening hit. The quality of a lead compound is akin to field position in a soccer match; it is critical to success. Losing possession in your own defensive half is rarely cause for alarm. However, losing the ball just outside the penalty area drastically increases the opponent's scoring probability, prompting defenders to often commit a tactical foul to halt the attack. Lead optimization operates on the same principle: if the starting lead is a random compound, even a single minor suboptimal property can eliminate 99.9% of your potential derivative compounds.

The molecular mechanism of MMV688533 remains unclear, which could be a significant drawback. From a structural perspective, the 2-pyridylamide moiety, derived from a guanidine group, serves as a reasonable bioisostere; however, it may also function as a metal-chelating group, potentially causing certain complications in the human body. Although the alkyne group derived from a diazo moiety is more stable than the diazo group itself, it remains a metabolic hotspot, and the ketone group formed upon oxidation may also be toxic. Fortunately, this drug does not require long-term administration, so the safety requirements are relatively lower. Malaria is a severe disease, but regrettably, it is also a neglected disease. The discovery of this drug candidate by these scientists through a low-cost, highly creative approach is commendable and serves as a valuable model for other pharmaceutical companies. While Metro-Goldwyn-Mayer (MGM) has undoubtedly produced many classic blockbusters, Blumhouse, with its low-cost business model, has also released several influential films over the past decade. “The masses have boundless creativity,” and scientists are certainly no exception.