The cornerstone of current onchocerciasis control is mass drug administration with ivermectin, a regimen recommended for ten to fifteen years. The drug is microfilaricidal, meaning it kills the larval stage of the parasite, but it does not eliminate the adult worms that continue to reproduce. Long-term annual treatment alone has proven insufficient to interrupt transmission in several foci, including parts of Cameroon where transmission has continued despite more than fifteen years of community-directed treatment with ivermectin. The 2025 verification of Niger as the first African country to eliminate onchocerciasis demonstrates that elimination is achievable, but it also underscores the urgent need for safe, macrofilaricidal alternatives that can shorten elimination timelines and counter emerging resistance or sub-optimal drug response in the remaining endemic areas.

Enter a team of researchers led by Maraf Mbah Bake of the University of Yaoundé I, working with collaborators in Cameroon, Germany, South Africa, Iraq and Spain. Writing in the journal Discover Chemistry, the team describes a systematic computational hunt for inhibitors of two detoxification enzymes from O. volvulus, using the ConMedNP library, a curated collection of roughly 3,500 secondary metabolites isolated from Central African medicinal plants. Their strategy combined ADMET-based filtering, tiered molecular docking, MMGBSA binding-energy rescoring, pharmacological activity prediction and 200-nanosecond molecular dynamics simulations, a pipeline designed to separate genuine binders from computational noise.

The molecular targets were the sigma-class and pi-class glutathione S-transferases of the parasite, known as Ov-GST1 and Ov-GST2. These enzymes conjugate glutathione to hydrophobic electrophiles, shielding the worm from oxidative damage and facilitating the excretion of xenobiotics, including drugs. Three GST isoforms have been characterized in O. volvulus, but the sigma and pi classes are particularly attractive because they underpin the parasite’s survival under oxidative stress. Crucially, the two isoforms differ structurally: Ov-GST1 possesses a larger, more solvent-exposed and flexible substrate-binding pocket, whereas Ov-GST2 has a smaller, more rigid cavity with greater substrate selectivity. These differences offered the researchers a structural basis for ligand selectivity that their screening pipeline was designed to exploit.

The workflow began with the crystal structures of Ov-GST2, co-crystallized with the inhibitor S-hexylglutathione, and Ov-GST1, co-crystallized with glutathione, retrieved from the Protein Data Bank. Each structure was carefully prepared, with protonation states assigned at physiological pH and restrained energy minimization performed using the OPLS3 force field. All 3,500 ConMedNP compounds were then profiled with QikProp against descriptors calibrated to the properties of 95 percent of approved drugs, including solubility, permeability, polar surface area and oral absorption. Docking proceeded through three sequential tiers of increasing stringency, high-throughput virtual screening, standard precision and extra precision, ultimately shortlisting ten hits against Ov-GST2 and eight against Ov-GST1.

A critical validation step lent credibility to the entire exercise. The researchers redocked the co-crystallized native ligands into their respective receptors under identical extra-precision settings, obtaining heavy-atom RMSD values of 1.023 angstroms for S-hexylglutathione and 0.954 angstroms for glutathione, both comfortably below the 2.0-angstrom threshold conventionally accepted as evidence of an accurate docking protocol. The native ligands also reproduced the expected hydrogen bonds with key residues such as Ser63, Gln49, Gln62 and Arg95 in Ov-GST2, and Glu87, Ser88, Trp63 and Tyr32 in Ov-GST1, matching previously reported experimental findings. With the protocol thus anchored, the team applied MMGBSA rescoring, an implicit-solvent estimate of binding free energy more discriminating than the empirical docking score, to rank the shortlisted hits.

Four compounds with the most favorable combined docking, MMGBSA and ADMET profiles advanced to the molecular dynamics stage: AN_UY_186_1 and AN_UY_088 against Ov-GST2, and BMC_00091 and SO_UY_018 against Ov-GST1. The two Ov-GST2 hits are homoisoflavanones, a subclass of flavonoids whose 4H-chromen-4-one core packs against the hydrophobic floor of the enzyme’s H-site while their 7-hydroxyl and methoxy substituents donate hydrogen bonds to the backbone of Leu50, and their C3 benzyl group engages Phe38 through pi-pi stacking. Strikingly, this pharmacophore mirrors the binding mode reported for antibacterial homoisoflavanones isolated from Hyacinthaceae species in 2007, suggesting a recurring chemical logic rather than a computational accident.

The 200-nanosecond simulations, run in Desmond with the OPLS4 force field in physiological salt conditions, revealed clear winners. AN_UY_088 held its position within the Ov-GST2 active site with protein backbone RMSD oscillating between 1.4 and 2.4 angstroms and ligand RMSD between 3 and 5 angstroms, forming persistent hydrogen bonds with Tyr7 and pi-pi stacking with Phe38. On the sigma-class side, SO_UY_018 proved the most stable complex, maintaining hydrophobic contacts with Phe123 and Ile127 and a positively charged interaction with Arg38 across roughly a third of the simulation. A Bayesian activity-spectrum analysis using PASS further corroborated the scaffold-level plausibility of the hits, predicting antibacterial, antiparasitic, anthelmintic and anti-inflammatory probabilities consistent with known pharmacophores.

Perhaps the most intriguing finding is the convergence with the team’s own prior work. In a 2024 study, the same group screened the South African Natural Compounds Database, a chemically and geographically distinct library of about 600 compounds, against Ov-GST2 and again landed on homoisoflavanones. That the same scaffold class is independently selected against the same target from two different African natural-product collections suggests the homoisoflavanone signature is reproducible across libraries rather than an artifact of any one collection’s composition. Meanwhile, the best Ov-GST1 lead, SO_UY_018, is not a homoisoflavanone but a larger, more extended scaffold that exploits the sigma-class enzyme’s distinctive Phe33, Phe123 and Ile127 hydrophobic patch, indicating that scaffold selection is target-dependent rather than library-dependent.

The authors are careful to frame these results as computational predictions, not proven cures. They acknowledge that MMGBSA values overestimate absolute affinities, that virtual screening is prone to false positives, and that even 200 nanoseconds of dynamics may undersample slow protein motions and rare unbinding events. Notably, the natural-product hits bind non-glutathionyl pharmacophores, meaning they are unlikely to be competitively displaced by the high intracellular concentration of glutathione, an advantage over substrate-mimetic peptide inhibitors, and their drug-like ADMET profiles make them plausible oral candidates, unlike the peptide native ligands. What happens next is the decisive test: recombinant enzyme inhibition assays, anthelmintic assays on O. volvulus microfilariae and adult worms, and in vitro ADMET studies will determine whether these digital leads, born from the flora of Central Africa, can graduate into the macrofilaricidal medicines that river blindness elimination efforts so urgently need.

Subject of Research: Computational identification of natural-product inhibitors of Onchocerca volvulus glutathione S-transferases

Article Title: Discovering potent Onchocerca volvulus inhibitors from the ConMedNP library through virtual screening, MMGBSA, and molecular dynamics simulations

Article References: Mbah Bake, M., Tsahnang Fofack, H. M., Petry, S., Tsague Meupe Bahoken, B., Bebga, G., Singh, T., Mbouombouo Ndassa, I., Mohammad-Salim, H., & de Julián-Ortiz, J. V. (2026). Discovering potent Onchocerca volvulus inhibitors from the ConMedNP library through virtual screening, MMGBSA, and molecular dynamics simulations. Discover Chemistry, 3(1), Article 465. https://doi.org/10.1007/s44371-026-00910-3

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00910-3

Keywords: Onchocerca volvulus, river blindness, ConMedNP library, virtual screening, MMGBSA, molecular dynamics, glutathione S-transferases, homoisoflavanones, natural products, drug discovery, neglected tropical diseases, ADMET

The research, led by an international team spanning institutions in the United States, Europe, and West Africa, pooled participant-level data from three field studies conducted in 2023 in Mozambique, Ghana, and Benin. Rather than evaluating each test in isolation, the investigators brought together individuals tested across all three countries, creating a combined dataset large enough to support sophisticated statistical modeling. The tests under scrutiny included the commercially available SD BIOLINE Ov16 rapid diagnostic test, which has been widely deployed in onchocerciasis mapping exercises, and two novel assays developed more recently: the DDTD rapid diagnostic test and the GADx rapid diagnostic test. All three are designed to detect antibodies to the Ov16 antigen, a marker of exposure to the parasitic worm that causes river blindness.

The central methodological challenge the researchers confronted is one that plagues much of diagnostic science in neglected tropical diseases: there is no perfect reference standard against which a new test can be judged. The gold standard for confirming an O. volvulus infection involves detecting microfilariae in skin snips, a procedure that is invasive, technically demanding, and critically insensitive in areas where infection levels have been driven down by years of treatment. In low-prevalence settings, a skin snip examination can miss the vast majority of true infections, making it a poor benchmark. Serological tests that detect antibodies offer a more practical alternative, but evaluating their accuracy without a definitive gold standard requires a different analytical approach altogether.

Enter the Bayesian latent class model, the statistical engine at the heart of this study. Latent class models treat the true infection status of each participant as an unobserved, or latent, variable, and then use the patterns of agreement and disagreement among multiple imperfect tests to infer both the true prevalence of infection and the sensitivity and specificity of each test simultaneously. The Bayesian framework adds prior information, formal mathematical expressions of what is already known or believed about test performance before the data are examined. By running the models under multiple specifications, including different priors reflecting laboratory-based and field-based expectations, the researchers could assess how sensitive their conclusions were to the assumptions embedded in the analysis. This approach, while computationally intensive, avoids the circular reasoning that arises when an imperfect test is treated as a perfect reference.

The headline finding concerns the GADx rapid diagnostic test, which emerged as the clear sensitivity leader across every model specification the team examined. Posterior median estimates of its sensitivity ranged from 92.0 percent to 92.8 percent, consistently clearing the 89 percent threshold recommended by the World Health Organization for tests used in decisions to stop mass drug administration. In practical terms, this means the GADx assay missed fewer than one in ten true antibody-positive cases in the studied populations, a level of performance that brings it meaningfully closer to the reliability that elimination programs require. The consistency of this result across alternative model assumptions lends considerable weight to the conclusion, since a finding that survives multiple analytical specifications is far more robust than one that depends on a single set of choices.

The performance of the other two tests tells a more nuanced story. The SD BIOLINE Ov16 test, the only commercially available option among the three, produced posterior median sensitivity estimates above the 89 percent threshold in most models, but fell to 83.2 percent under the field-based prior, a specification that reflects performance expectations drawn from real-world deployment conditions rather than idealized laboratory settings. This inconsistency echoes earlier reports that the SD BIOLINE test shows variable sensitivity when used on whole blood in field conditions. The DDTD rapid diagnostic test, a multi-antigen assay, demonstrated lower sensitivity overall, with posterior median estimates ranging from 86.6 percent to 88.4 percent, placing it just below the recommended threshold. Notably, the researchers tested alternative definitions of a positive result for the multi-antigen DDTD test and found that these did not meaningfully alter its estimated performance, suggesting the result was not an artifact of how positive readings were scored.

Specificity, the ability of a test to correctly identify people who are not infected, presented a different kind of problem. All three tests achieved consistently high specificity estimates, with the highest posterior median reaching 98.8 percent. That figure sounds impressive, and in most clinical contexts it would be. But the WHO-recommended threshold for tests supporting decisions to stop mass drug administration is 99.8 percent, a demanding standard that reflects the consequences of false positives in low-prevalence settings. When transmission has been reduced to very low levels, even a small false-positive rate can generate a misleading picture of ongoing transmission, potentially triggering unnecessary rounds of treatment, wasted resources, and delayed declarations of elimination. None of the evaluated tests, including the high-performing GADx assay, reached that specificity bar on its own.

The implications of this gap are significant for the global elimination agenda. Onchocerciasis programs increasingly rely on serological surveys of children, who should show little or no antibody evidence of exposure if transmission has been interrupted, to guide decisions about stopping treatment. A test that combines high sensitivity with extremely high specificity is essential for these surveys to be trustworthy. The study’s findings suggest that while the novel rapid tests, particularly the GADx assay, represent genuine progress over the existing commercial option, no single test currently available can shoulder the entire burden of an elimination decision. The authors conclude that improved diagnostic tools or complementary testing strategies will be needed, which could involve combining tests in sequence, using different sample types, or integrating serological data with entomological surveillance of the blackfly vectors that transmit the parasite.

The geographic breadth of the underlying data strengthens the study’s relevance across the African continent, where the vast majority of onchocerciasis burden is concentrated. Field studies in Mozambique, Ghana, and Benin captured diverse epidemiological settings, from areas with historically intense transmission to those where control efforts have been sustained for many years. Pooling participant-level data, rather than combining summary statistics from separate analyses, allowed the Bayesian models to account for heterogeneity across sites and to borrow statistical strength from the full dataset. This design choice matters because diagnostic performance can vary with factors such as infection intensity, population age structure, and the prevalence of other parasitic infections that might cross-react with the Ov16 antigen.

For the elimination community, the study offers both reassurance and a call to action. The demonstration that rigorous, assumption-aware evaluation of rapid diagnostic tests is feasible using Bayesian latent class methods provides a template for assessing future diagnostics, not only for onchocerciasis but for other diseases approaching elimination where gold standards are similarly lacking. At the same time, the finding that no evaluated test meets the specificity threshold on its own underscores that the final mile of the river blindness campaign will demand continued investment in diagnostic development. The GADx test’s sensitivity performance marks a milestone worth celebrating, but the road to confident, evidence-based decisions about stopping mass drug administration will require tools that are both more sensitive and more specific than anything currently in the field. Until then, program managers must weigh these imperfect instruments carefully, knowing that the health of millions and the credibility of the elimination enterprise rest on getting the answer right.

Subject of Research: Diagnostic accuracy of Ov16 rapid diagnostic tests for onchocerciasis elimination using Bayesian latent class models

Article Title: Assessing diagnostic accuracy of onchocerciasis rapid diagnostic tests using Bayesian latent class models

Article References: Norman, J., Bassabi-Alladjie, N.-M., Boko-Collins, P. M., de Souza, D. K., Gass, K., Hamill, L., Langa, J., Moore, C., Mucato, N., Nala, R., Sullivan, S., & Giorgi, E. (2026). Assessing diagnostic accuracy of onchocerciasis rapid diagnostic tests using Bayesian latent class models. PLOS Neglected Tropical Diseases, 20(10), e0013954. https://doi.org/10.1371/journal.pntd.0013954

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0013954

Keywords: onchocerciasis, river blindness, rapid diagnostic tests, Bayesian latent class models, Ov16 antigen, diagnostic accuracy, mass drug administration, neglected tropical diseases, GADx, SD BIOLINE, elimination, serology

The scale of the problem ENDPOINT addresses is difficult to overstate. Lymphatic filariasis and onchocerciasis are both caused by filarial parasitic worms transmitted to humans by insect vectors — mosquitoes in the case of lymphatic filariasis and blackflies in the case of onchocerciasis. Together, these infections affect an estimated 78 million people, with a further one billion judged to be at risk. Lymphatic filariasis, historically known as elephantiasis, damages the lymphatic system and produces chronic swelling of the limbs and genitals, profound disfigurement and social stigma. Onchocerciasis, or river blindness, is the second leading infectious cause of blindness worldwide and also causes severe, debilitating skin disease. Beyond the direct clinical burden, both diseases significantly undermine economic prosperity in endemic communities, trapping affected households in cycles of poverty that mass drug administration alone has struggled to break.

As a product development partnership, ENDPOINT occupies a distinctive niche in the global health architecture. Rather than conducting basic research or delivering existing interventions, PDPs are structured to advance a pipeline of candidate products — in this case innovative diagnostics and treatments — while simultaneously generating evidence on their acceptability and feasibility within affected communities and health systems. The programme will also map potential policy and regulatory pathways, a step that is often neglected in early-stage development but which determines whether a promising tool ever reaches the patients who need it. This integrated approach reflects a growing recognition within the neglected tropical disease field that technical efficacy is only one ingredient of elimination; a diagnostic that communities will not use, or a drug regimen that health systems cannot deliver, will not move the needle regardless of its laboratory performance.

Professor Joseph Turner, co-director of LSTM’s Centre for Drugs and Diagnostics and research director of the partnership, framed the funding as a critical endorsement of the institution’s filarial portfolio. He expressed immense gratitude for what he described as a valuable FCDO investment in the CDD iiCON filarial NTDs product development portfolio, noting that the pipeline of diagnostic and therapeutic candidates had been selected specifically to overcome barriers that currently stand in the way of lymphatic filariasis and onchocerciasis elimination. Crucially, he emphasised that candidate products will be evaluated not only for effectiveness but also for their acceptability to the communities that would use them, with the results feeding directly into the refinement and acceleration of their onward development. That feedback loop between end users and product developers is one of the defining features of the ENDPOINT model.

The partnership’s portfolio comprises three complementary projects, each targeting a different bottleneck in the elimination effort. The first is a wearable microwave biosensor diagnostic intended to support non-invasive detection and surveillance of lymphatic filariasis in Nepal. Conventional diagnosis of filarial infections typically relies on blood samples or antigen tests that must be administered by trained personnel, which complicates large-scale surveillance in remote endemic areas. A wearable biosensor that can detect infection markers without invasive sampling could transform monitoring, allowing health authorities to track transmission in real time and to verify whether elimination targets have genuinely been achieved — a requirement that becomes increasingly important as countries approach the endgame of their elimination programmes.

The second project repurposes the oral antibiotic fusidic acid as a shorter-course treatment for onchocerciasis, building on the LSTM-led FAME study. Repurposing established drugs is an attractive strategy in neglected tropical disease research because decades of clinical use provide a well-characterised safety profile, and existing manufacturing and regulatory infrastructure can dramatically shorten the path to deployment. Fusidic acid belongs to a class of antibiotics that act against the Wolbachia bacteria, endosymbionts that many filarial worms depend upon for their survival and fertility. Depleting Wolbachia with antibiotics renders the adult worms sterile and ultimately kills them, addressing the root of the infection rather than merely the larval stages targeted by the standard drug ivermectin. A shorter treatment course would make antibiotic therapy far more practical for mass deployment in resource-limited settings.

The third project, conducted in the United Kingdom, involves the early development of a new class of fast-acting anti-Wolbachia drug candidates. These compounds hold potential to treat or prevent onchocerciasis and lymphatic filariasis, and — notably — veterinary zoonotic filariasis as well. Zoonotic filarial infections, in which parasites normally circulating in animals infect humans, represent an underappreciated reservoir that could complicate elimination efforts; a drug class effective across both human and animal filariae would therefore carry strategic value beyond the two headline diseases. Fast-acting anti-Wolbachia agents would also address one of the principal limitations of existing antibiotic regimens, which require weeks of daily dosing and are consequently ill-suited to community-wide campaigns.

Dr Rachael Thomson, ENDPOINT’s chief executive, described the funding award as a real achievement for both ENDPOINT and LSTM, saying that the investment strengthens the global research pipeline for neglected tropical diseases and reinforces the partnership’s commitment to delivering equitable, impactful solutions for affected communities. Her emphasis on equity speaks to a persistent criticism of global health research, in which diseases concentrated in low-income countries have historically attracted a fraction of the funding devoted to conditions prevalent in wealthy nations. By embedding partners in Nepal and Cameroon as full participants in product development rather than merely as trial sites, ENDPOINT aims to strengthen national research and development capacity in endemic countries, leaving behind durable scientific infrastructure alongside the products themselves.

ENDPOINT does not stand alone. It dovetails with FAME, a complementary clinical trial funded by a £4.9 million award from the European and Developing Countries Clinical Trials Partnership, with additional support from the Drugs for Neglected Diseases initiative. FAME is generating critical evidence on the potential of repurposing fusidic acid to treat onchocerciasis and on the future uptake of antibiotic-based tools for filarial disease elimination more broadly. Taken together, ENDPOINT and FAME represent nearly £9.4 million in new investment, a figure that reaffirms LSTM’s long-standing leadership in research and development for filarial neglected tropical diseases. The pairing of an early-stage product development partnership with a late-stage clinical trial is itself a deliberate design choice, ensuring that discoveries made under ENDPOINT can be shepherded along a defined development pathway rather than stalling at the so-called valley of death between laboratory and clinic.

The announcement arrives at a pivotal moment for the neglected tropical disease community. The World Health Organization’s road map for 2021 to 2030 set ambitious elimination targets for lymphatic filariasis and onchocerciasis, and while mass drug administration has driven down transmission in many endemic countries, progress has stalled in others where existing tools are insufficient to finish the job. New diagnostics capable of confirming interruption of transmission, and new treatments capable of killing or sterilising adult worms, are widely regarded as the missing instruments for the final phase of elimination. By combining cutting-edge technologies such as wearable biosensing and novel anti-Wolbachia pharmacology with strong in-country partnerships and a systematic focus on acceptability, feasibility and regulatory readiness, ENDPOINT aims to generate the high-quality evidence needed to de-risk scalable solutions. For the 78 million people already living with these diseases and the billion more at risk, the partnership represents a tangible step toward tools that could finally close the chapter on two of humanity’s most ancient afflictions.

Subject of Research: Development of new diagnostics and treatments for the filarial neglected tropical diseases lymphatic filariasis and onchocerciasis

Article Title: LSTM announces new £4.5 million partnership to tackle neglected tropical diseases

Article References: LSTM announces new £4.5 million partnership to tackle neglected tropical diseases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: neglected tropical diseases, lymphatic filariasis, onchocerciasis, Liverpool School of Tropical Medicine, ENDPOINT, Wolbachia, fusidic acid, diagnostics, drug development, UK aid, FCDO, river blindness