Beyond conventional small molecule drug discovery

Introduction

Since the commercialisation of aspirin by Bayer in 1899, pharmaceutical drug discovery has primarily focused on the development of small molecules drugs. Generally, small  molecule drugs work by interacting with specific protein targets, disrupting their natural  activity to produce a therapeutic effect. To contextualise the success of small molecule  drug discovery, the projected growth of the market is expected to reach $117.05 billion by 2030. 

However, conventional small molecule synthesis can be limited by the need for  accessible protein binding sites and the potential for unwanted off target effects.  Consequently, in the last 25 years, scientists have begun exploring alternative  therapeutic approaches, particularly at the interface of chemistry and biology. Therefore, this article will seek to introduce three emerging therapeutic modalities in  pharmaceutical research and the synthetic chemistry behind their development.  

Oligonucleotides

Oligonucleotides are short single or double stranded fragments of DNA or RNA. Two  important classes of therapeutic oligonucleotides are antisense oligonucleotides  (ASOs) and small interfering RNAs (siRNAs), which use different mechanisms to prevent  the expression of disease-associated proteins.

ASOs are designed with a complementary base sequence to a target mRNA. The single  strand can then bind selectively to this sequence in the target RNA, altering its  processing or preventing it from being translated and forming new disease proteins.  

The mechanism of siRNA is distinct but similarly relies on the sequence-specific  recognition of mRNA. Following cellular uptake, the double stranded oligonucleotide is initially loaded into the RNA–induced silencing complex (RISC). This then discards one  of the strands which allows the other to bind complementarily to a specific mRNA strand (Figure 1).  

Synthetically, many therapeutic oligonucleotides are produced using solid phase  oligonucleotide synthesis (SPOS). SPOS uses phosphoramidite chemistry to assemble  nucleotides sequentially through a repeated four-step synthesis (Figure 2).  

Although individual coupling steps can proceed with high efficiency, the cumulative yield decreases as the oligonucleotide becomes longer because each additional nucleotide requires another synthetic cycle. This has encouraged research into alternative approaches, including hybrid enzymatic methods for oligonucleotide synthesis. This approach may offer advantages in process efficiency and sustainability, reducing the reliance on acetonitrile and enabling synthesis under milder conditions to avoid enzyme denaturation.

Antibody Drug Conjugates (ADCs)

Antibody drug conjugates (ADCs) are therapeutic compounds that consist of a monoclonal antibody, a chemical linker and a cytotoxic drug payload. Biologically,  ADCs use the antibody to bind selectively to an antigen expressed on the surface of a  target cell. This binding can cause internalisation of the ADC, allowing the cytotoxic  payload to be delivered into the cell (Figure 3).

Synthetically, ADCs do not have one universal synthetic process, unlike oligonucleotides which can be made using a relatively standardised SPOS process. Instead, the antibody, linker and payload can be prepared separately before being combined via a range of conjugation strategies. Generally, linkers are attached to antibodies via conjugation with amino acid residues present on the antibody. For example, gemtuzumab ozogamicin, the first ADC approved in the United States, uses conjugation through surface lysine residues on the antibody.

Linkers are specially synthesised to remain sufficiently stable during circulation while  allowing the payload to be released at the desired site. Gemtuzumab ozogamicin is an  example of an ADC containing a cleavable linker, which incorporates a hydrazone which  is susceptible to hydrolysis under the more acidic conditions encountered following  cellular uptake (Figure 4).  

Proteolysis Targeting Chimeras (PROTACs)

Proteolysis Targeting Chimeras (PROTACs), like ADCs, are compounds composed of  three distinct parts: a protein binding moiety, a chemical linker and E3 ligase binding  ligand. PROTACs use their protein binding moiety to attach to the target disease protein.  The linkers are designed to be a specific length to enable the E3 ligase binding ligand to recruit an E3 ubiquitin ligase.  

Once bound, the E3 ligase enzyme is brought within proximity to the target protein  which it labels with a ubiquitin tag. Following sufficient ubiquitination, the target protein  is recognised and degraded by the cell's proteasome (Figure 5). 

Synthetically, PROTACs are like ADCs in that there is no universal synthetic route.  Instead, a variety of established organic chemistry reactions can easily be applied to  PROTAC synthesis as in the case of newly marketed Vepdegestrant (Figure 6). In this  synthesis, transformations including reductive amination, acid-catalysed cyclisation  and alkene reduction were combined with asymmetric synthetic methods to yield the  final product.  

Conclusion

While conventional small-molecule drugs remain a pillar of pharmaceutical research  and development, emerging therapeutic modalities are expanding the range of  biological processes that can be manipulated by medicinal chemistry. ADCs  demonstrate how chemical linkers and cytotoxic payloads can be combined with the  targeting ability of antibodies, while PROTACs exploit the cell's endogenous protein degradation machinery to remove disease-associated proteins. Oligonucleotide  therapeutics provide another distinct approach by targeting RNA itself, with  applications extending beyond oncology to rare genetic and cardiovascular diseases. Together, these approaches highlight how combining synthetic chemistry with a  detailed understanding of cellular biology can provide innovative solutions for modern drug discovery.

Written by Antony Lee

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