that can cyclize peptides with two cysteine resi-
dues ( 51 ). Through combined application of a
ribozyme biocatalyst to enable unnatural amino
acid incorporation into peptides, and then bio-
orthogonal chemistry forcysteine cyclization
through that unnatural amino acid, the Suga lab
has developed an improved mRNA display plat-
form ( 52 ) that has demonstrated tremendous po-
tential to identify peptide ligands for challenging
targets. The merging of chemical synthesis and
biosynthesis within a common platform inspires
further exploration of cyclic peptide modality; the
introduction of selection pressures and forced
evolution into this platform begins to resemble
aspects of natural product generation that has
historically inspired both organic synthesis and
drug discovery.
Technologies to accelerate innovation
High-throughput experimentation
Given the need to invent and rapidly deliver
medicines to patients, the pharmaceutical indus-
try must invest in capabilities with the potential
to radically accelerate the discovery and indus-
trialization of transformative synthetic method-
ologies. High-throughput screening in biology
has been the foundation of hit discovery for
decades, and in recent years, the pharmaceu-
tical industry has strategically invested in the
creation of high-throughput experimentation
(HTE) tools for chemistry that enable scientists
to test experimental hypotheses with hundreds of
arrayed experiments ( 53 ).Inthesametimeframe
required for traditional single-reaction evalua-
tion, the different parameters that determine
reaction outcome, discrete variables (catalysts,
reagents, solvents, additives), and continuous
variables (temperatures, concentrations, stoi-
chiometries) can be holistically explored in par-
allel ( 54 ). As a result, the synthetic chemist now
has access to exponentially larger amounts of
experimental data than ever before. One recent
example of the use of end-to-end HTE in process
development was the discovery and develop-
ment of an organo-catalyzed, enantioselective,
aza-Michael reaction for the commercial man-
ufacture of the antiviral letermovir (Fig. 5) ( 55 ).
In this work, a series of efficient synthetic path-
ways were envisioned by chemists and key
transformations were evaluated in parallel using
HTE. The emergence of an H-bonding catalysis
mechanism was initially discovered with mod-erate enantioselectivity and low conversion using
chiral phosphoric acids. Rapid evaluation of a
large number of diverse scaffolds with H-bonding
capability in this transformation resulted in the
discovery of an efficient and highly selective bis-
sulfonamide catalyst. Further HTE work enabled
the mechanistic understanding of the transfor-
mation, leading to optimization of both the cat-
alyst structure and definition of optimal processing
conditions. In this study and in many others ( 56 , 57 ),
novel bond-forming reactions were conceived by
scientists, discovered through HTE, and then rap-
idly industrialized for the commercial manufac-
ture of late-stage drug candidates.
HTE tools have also begun to have an impact
in drug discovery ( 58 ). As new catalytic methods
emerge that redefine which bonds can be forged,
the breadth of the resulting substrate scope is
poorly understood, as most test substrates com-
monly demonstrated in the literature are simple
and not representative of the complex func-
tionality common in drug candidates. Pre-dosed,
reaction-specific HTE screening kits, contain-
ing a lab’s most successful and general catalyst
systems, are used in discovery chemistry labs
to enable the rapid identification of reactionCamposet al.,Science 363 , eaat0805 (2019) 18 January 2019 5of8
Fig. 6. Application of computational modeling to new catalyst design.
RESEARCH | REVIEW
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