Amino Acids

Amino acids occupy a foundational position in medicinal chemistry and drug discovery, serving simultaneously as primary pharmacophores, synthetic building blocks, metabolic mimetics, and the constituent units of the increasingly important class of therapeutic peptides. Their defined stereochemistry, complementary amine and carboxylic acid functionality, and diversity of side chains spanning hydrophobic, polar, charged, and aromatic character provide an exceptionally rich starting point for structure-activity relationship exploration. In small-molecule drug discovery, unnatural amino acids are routinely incorporated into peptidomimetic scaffolds to improve target affinity, resist enzymatic degradation, and fine-tune ADMET properties relative to their natural counterparts. The alpha-amino acid motif, with its geometrically defined alpha-carbon, hydrogen bond donor amine, and hydrogen bond acceptor carboxylate, is a bioisostere for numerous natural substrates of enzyme active sites, and this molecular mimicry underpins many classes of protease inhibitors, transport protein substrates, and enzyme co-factor mimics. Unnatural amino acids with constrained side chains, beta-substitution, or N-methylation are particularly valued for their ability to restrict peptide backbone conformation, enforce bioactive conformations, and block metabolic degradation points. At a broader level, amino acids are indispensable precursors for active pharmaceutical ingredient manufacturing, providing enantiopure chiral pools for the asymmetric synthesis of complex drug candidates without requiring expensive chiral catalysis.

Two FDA-approved drugs illustrate the centrality of amino acid chemistry in modern therapeutics. Daprodustat (Jesduvroq, GlaxoSmithKline), approved in February 2023 as the first-in-class HIF prolyl hydroxylase inhibitor and the first new treatment for anaemia of chronic kidney disease approved in the US in over 30 years, uses a glycine-derived acetic acid group as its core pharmacophore. The glycinamide carbonyl directly chelates the catalytic iron(II) of the PHD enzyme active site in a six-membered bidentate interaction that mimics the binding of N-oxalylglycine, the endogenous inhibitor: this amino acid-derived warhead is inseparable from the compound's mechanism. Nirmatrelvir (as Paxlovid, Pfizer), the first oral SARS-CoV-2 main protease inhibitor to receive FDA approval, first as Emergency Use Authorization in 2021 and full approval in 2023, is a peptidomimetic built directly from amino acid fragments. It incorporates a glutamine-derived bicyclic lactam at the P1 position, a dimethylcyclopropylproline residue at P2, and a trifluoromethyl-substituted leucine surrogate at P3: each of these amino acid-derived elements was optimised through iterative SAR informed by X-ray crystallography of the Mpro active site, and the compound's selectivity for the viral cysteine protease over host serine proteases depends critically on the precise geometry imposed by these amino acid-derived scaffolds.

Semaglutide (Ozempic/Wegovy/Rybelsus, Novo Nordisk) has emerged as one of the most clinically impactful medicines of the modern era, and its design exemplifies the transformative power of amino acid-based drug engineering. Semaglutide is a 31-amino acid peptide sharing 94% structural homology with the endogenous incretin hormone GLP-1, but modified at three critical positions: an alpha-aminoisobutyric acid (Aib) substitution at position 8 prevents dipeptidyl peptidase-4 (DPP-4)-mediated cleavage; arginine replaces lysine at position 34 to improve stability; and lysine at position 26 is acylated via a hydrophilic linker with a C18 fatty diacid to promote albumin binding, extending plasma half-life to approximately seven days and enabling once-weekly subcutaneous dosing. These amino acid-level modifications collectively transform a hormone with a two-minute in vivo half-life into a clinical agent capable of driving 15% or greater body weight reduction, a breakthrough in obesity pharmacotherapy that has directly stimulated a new generation of multi-receptor GLP-1 co-agonists including tirzepatide.

In organic synthesis, amino acids are substrates and products of several landmark named reactions. The Strecker synthesis converts an aldehyde to an alpha-aminonitrile through reaction with ammonia and hydrogen cyanide, followed by hydrolysis, and provides one of the most concise routes to alpha-amino acids from simple carbonyl precursors; enantioselective variants using chiral Lewis acid catalysts now provide access to optically enriched unnatural amino acids. The Bucherer-Bergs reaction condenses a ketone with potassium cyanide and ammonium carbonate to form a hydantoin that is hydrolysed to the corresponding alpha-amino acid. The Erlenmeyer-Plochl azlactone synthesis converts N-acylglycine to arylglycine and beta-aryl amino acid derivatives via azlactone intermediates under basic or acidic conditions. Solid-phase peptide synthesis (SPPS), pioneered by Merrifield and enabled by Fmoc or Boc amino acid building blocks, provides access to peptide chains of defined sequence through iterative coupling-deprotection cycles and remains the primary manufacturing route for therapeutic peptides.

Emerging synthetic techniques are opening new avenues for the use of amino acids as both substrates and building blocks. In photochemistry, visible-light photoredox catalysis has established alpha-amino acids as abundant radical precursors through oxidative decarboxylation: under iridium or organic photoredox conditions, amino acids generate alpha-amino radicals that can be coupled with aryl halides via nickel co-catalysis in the MacMillan dual-catalysis platform to produce enantioenriched benzylic amines in a single step from amino acid feedstocks, directly converting biomass into drug pharmacophores. Electrochemically, the decarboxylative late-stage functionalization of amino acid derivatives has been achieved through anodic oxidation, enabling site-selective carbon-heteroatom bond formation at the alpha-carbon without racemisation, and providing a mild and scalable alternative to stoichiometric oxidants for the preparation of modified amino acid building blocks relevant to peptidomimetic drug synthesis.

Our catalogue of amino acids includes both proteinogenic and unnatural variants with a diverse range of side chains, protected forms for Fmoc and Boc solid-phase peptide synthesis, and functional group-bearing derivatives to support medicinal chemistry programmes, SAR investigations, and the synthesis of peptidomimetic drug candidates.