Chemical antibodies show promise against viruses and neglected tropical diseases

Short synthetic strands of DNA or RNA known as aptamers are emerging as versatile tools for detecting and treating viral infections and parasitic neglected tropical diseases, according to a review published in Discover Medicine on 26 October 2026. The authors, led by Neha Bhandari and Charu Gupta, survey three decades of aptamer research against pathogens including SARS-CoV-2, HIV-1, hepatitis viruses, Leishmania, Trypanosoma cruzi and Plasmodium falciparum, and conclude that recent studies have delivered improved binding affinities, lower detection limits and potent inhibitory effects in preclinical models, while clinical translation remains limited.

Aptamers, sometimes called chemical antibodies, are single-stranded nucleic acids typically 15 to 100 nucleotides long that fold into unique three-dimensional shapes and bind their targets with antibody-like specificity through a lock-and-key mechanism. Their recognition surfaces are built from structural motifs such as stem-loops, pseudoknots, bulges and G-quadruplexes, and binding is mediated by hydrogen bonds, electrostatic interactions, van der Waals forces and pi-pi stacking, often following an induced-fit transition upon target engagement. Compared with antibodies, they are cheaper to produce, show reduced batch-to-batch variability, carry low immunogenicity, penetrate tissue more readily because of their small size, and can be synthesized in large quantities and stored for extended periods without significant loss of activity.

The review highlights that these properties make aptamers particularly attractive for point-of-care testing in resource-limited settings where cold-chain infrastructure is scarce, since they remain stable at room temperature. DNA aptamers are less expensive to produce and are considered more stable than their RNA counterparts, while RNA aptamers fold into robust three-dimensional conformations and show improved tissue penetration. Chemical modifications at the 2-prime position of ribose, commonly 2-prime-fluoro or 2-prime-O-methyl groups, generally increase resistance to nuclease degradation, and partially modified single-stranded RNA aptamers have been reported to extend their half-life by approximately 5 to 15 hours compared with unmodified RNA molecules.

Aptamers are generated through Systematic Evolution of Ligands by Exponential Enrichment, or SELEX, a semi-evolutionary technique pioneered by Tuerk and Gold that requires multiple in vitro rounds of selection, affinity purification and amplification from a starting pool of roughly 10 to the 12th to 10 to the 15th random sequences. Incubation parameters such as ratio, temperature and ionic strength are tuned to maximize binding, unbound sequences are removed by stringent washing, and target-specific oligonucleotides are recovered by magnetic separation, column chromatography or centrifugation before PCR amplification. Negative selection phases remove cross-reactive binders, and variants such as Toggle SELEX and Cell-SELEX refine specificity or allow selection against targets in their native environment. Over the last three decades the field has progressed from classical protein-based selections requiring numerous rounds to high-throughput, AI-assisted and microfluidic platforms, with early conventional SELEX reporting micromolar to nanomolar binders and more recent studies reporting sub-nanomolar to picomolar dissociation constants.

Against HIV-1, the review traces a lineage of aptamer work beginning in 2000, when Yamamoto and colleagues screened RNA aptamers targeting the viral Tat protein and found one that bound TAR RNA with 133-fold higher affinity than the TAR RNA aptamers themselves, inhibiting Tat-dependent transcriptional transactivation in vitro and impeding viral proliferation in a murine model. More recently, Gruenke and colleagues used branched SELEX in 2024 to produce structurally diverse aptamers against the HIV-1 capsid protein, identifying aptamers that bound the capsid lattice and promoted capsid elimination from cell lysates without modifying the virus or host. Valades-Alcaraz and others generated two single-stranded DNA aptamers against a cross-reactive peptide of HIV-1 protease, confirming binding by enzyme-linked oligonucleotide assays and providing a proof of concept for early detection systems targeting conserved viral regions.

For SARS-CoV-2, aptamer platforms offered stable, rapid detection from standard patient samples when reagent shortages, RNA degradation and cross-reactivity hampered RT-PCR, ELISA and lateral flow assays. Song and colleagues combined machine learning with aptamer screening against ACE2 to propose the 51- and 67-nucleotide aptamers CoV2-RBD-1C and CoV2-RBD-4C, and Sun and colleagues assembled three such aptamers into a spherical neutralizing cocktail on gold nanoparticles termed SNAP, which significantly enhanced blockade of viral entry by preventing interaction between the virus and ACE2. Pun and colleagues developed SNAP1, a DNA aptamer with a dissociation constant below 80 nanomolar for the spike protein N-terminal domain, which detected UV-inactivated virus by lateral flow assay and ELISA with a limit of detection of 5 times 10 to the 5th copies per milliliter. Zhang and colleagues designed the dimeric aptamer DSA1N5, achieving picomolar affinity for the Alpha and Delta variants and the wild type and enabling electrochemical detection of 1 times 10 to the 3rd particles per milliliter in diluted saliva in under 10 minutes on gold electrodes. A circular bivalent DNA aptamer, cb-N-Apt17, showed superior stability and improved binding to the nucleocapsid protein of major variants, and a jumbled viro-SELEX approach in 2025 yielded aptamers AM016 and AM086 that improved sensitivity and reduced processing time in a two-step qPCR assay.

On the parasitic side, the review catalogs aptamers against kinetoplastids and apicomplexans. Homann and Göringer reported the first RNA aptamers specific to T. brucei in 1999, which bound with rapid association kinetics and cross-reacted with trypanosomal strains outside the initial screen, and later work showed these aptamers could serve as intracellular delivery vehicles via the parasite’s endosomal machinery. Nagarkatti and colleagues developed RNA aptamers against T. cruzi trypomastigotes by whole-cell SELEX, with Apt68 showing a dissociation constant of 8 to 25 nanomolar and a target uniquely expressed in T. cruzi. For Leishmania, aptamers against the KMP-11 membrane protein, the poly(A)-binding protein recognized at low nanomolar concentrations by three aptamers, and the H3 histone protein detected on Western blot, slot blot and ELONA platforms have been described. In malaria, RNA aptamers against the DBL1-alpha domain of PfEMP disrupted rosette formation in blood culture in a concentration-dependent manner between 33 and 387 nanomolar, while aptamers against plasmodium lactate dehydrogenase achieved a femtomolar limit of detection for recombinant PfLDH and PvLDH, equivalent to roughly a few parasites per microliter of blood.

Biosensor engineering translates these binding reagents into deployable diagnostics. Electrochemical aptasensors, which convert aptamer-target binding into changes in current, voltage, impedance or conductivity, have achieved limits of detection of 0.84 to 1 picomolar for P. falciparum lactate dehydrogenase on gold nanoparticle-graphene oxide nanocomposites and approximately 0.77 picomolar for P. falciparum glutamate dehydrogenase in human serum. A fluorescence sensor based on a chitosan-carbon dot nanocomposite quantified L. infantum at a limit of detection of 94 cells per milliliter, and colorimetric gold nanoparticle systems enabled naked-eye detection of P. vivax lactate dehydrogenase at 74 to 80 parasites per microliter. The review cautions, however, that electrochemical sensors are prone to signal drift and electrode fouling in complex clinical matrices such as whole blood and serum, fluorescent platforms face photobleaching and autofluorescence in tropical field conditions, and colorimetric methods trade sensitivity for robustness and cost, meaning no single transduction modality suits all neglected tropical disease applications.

The translational picture remains sobering. Most therapeutic aptamers for neglected tropical diseases are still at the in vitro or preclinical stage, and aptamer-drug conjugates that could deliver amphotericin B to infected macrophages or benznidazole to T. cruzi-infected cells have yet to demonstrate that aptamer-mediated delivery translates into actual uptake and enhanced antiparasitic efficacy. Only a limited number of aptamers have reached approved products, the most prominent being the FDA-approved Pegaptanib for age-related macular degeneration, whose subsequent withdrawal after reduced use illustrates the difficulties of aptamer drug development. Nuclease susceptibility and rapid renal clearance require chemical modification or conjugation with molecules such as cholesterol or PEG, and clinical evaluation of the PEGylated RNA aptamer pegnivacogin reported severe immediate allergic reactions associated with pre-existing anti-PEG antibodies, underscoring the need for immunogenicity assessment during development.

The authors also flag structural barriers beyond the laboratory. Unequal regional capacities in global upstream supply chains limit cost-effective end-to-end aptamer production in low- and middle-income countries, since solid-phase oligonucleotide synthesis depends on specialty reagents such as phosphoramidites and controlled-pore glass supports produced at scale by a small number of specialized suppliers concentrated in North America, Europe and East Asia. Few African countries have commercial-scale oligonucleotide manufacturing capacity, and importing aptamers or synthesis reagents adds shipping, customs and competition-related costs. The review argues that realizing the promise of low-cost aptamer diagnostics will require local reagent production, technology transfer and standardized validation protocols covering biological stability, specificity, reproducibility, manufacturability and regulatory feasibility, with artificial intelligence positioned to provision rather than substitute experimental SELEX as the field moves toward clinically viable platforms for viral and parasitic diseases.

Subject of Research: Aptamer-based diagnostics and therapeutics for viral and parasitic neglected tropical diseases

Article Title: Aptamers for precision diagnosis and therapy for viral infections and parasitic neglected tropical diseases

Article References: Bhandari, N., Kumar, M., Beg, M. A., Selvapandiyan, A., & Gupta, C. (2026). Aptamers for precision diagnosis and therapy for viral infections and parasitic neglected tropical diseases. Discover Medicine, 3(1), Article 165. https://doi.org/10.1007/s44337-026-00735-0

Image Credits: AI Generated

DOI: 10.1007/s44337-026-00735-0

Keywords: aptamers, SELEX, neglected tropical diseases, SARS-CoV-2, HIV, malaria, leishmaniasis, biosensors, point-of-care diagnostics, drug delivery, nuclease resistance, LMICs