application of decarboxylative alkylation chem-
istry to the C terminus of a protein substrate ( 48 )
offer new insights into achieving bio-orthogonal
and highly site-selective conjugation with com-
plex biomolecules (Fig. 4). These reactions take
advantage of local differences in basicity and
ionization potential respectively and, in doing so,
leverage the complexity that biopolymers offer.
Synthetic innovation and
therapeutic modalities
As these advances in synthetic, biorthogonal, and
biosynthetic chemistry merge, so too do our capa-
bilities to improve therapeutic modalities in the
space between synthetic small molecules and
expressed large monoclonal antibodies. Peptides,
oligonucleotides, and bioconjugates have been ad-
vanced particularly for biological targets deemed
“undruggable”by small-molecule and antibody
platforms. Advances in these chemistries inspire
new platforms and improve the breadth of bio-
logical targets that we can address. Two exam-
ples of innovation in therapeutic modalities
through synthetic and biosynthetic chemistry are
described below, although many others are being
invented in academic andindustrial settings.
In the first case, it has long been appreciated that
a critical element of the success of oligonucleotide-based therapies was the introduction of phos-
phorothioates into the oligo backbone, which
afforded improved stability to biological matrices
as well as improved membrane permeability
to aid with cytosolic delivery. Although these
and other improvements in stability and de-
livery have advanced the field and enabled
novel therapeutics to enter the clinic, many
oligo-based therapies require high doses to
overcome barriers to delivery, and their use is
limited by their toxicity. Further improvements
in stability and potency of the oligonucleotide
should contribute to a widening of the ther-
apeutic index and dose lowering. Interesting-
ly, the chemistry used to introduce stabilizing
phosphorothioates leaves each center as a mix-
ture of two P-stereoisomers. Therefore, most
clinical phosphorothioate-containing oligos that
have 20 base pairs are, in reality, a large mixture
of stereoisomers (2^19 ), each with different po-
tency and stability characteristics. The ability to
control phosphorothioate chemistry through an
oxazaphospholidine approach by Wada and col-
leagues ( 49 ) led to a practical and scalable plat-
form ( 50 ) for stereopure antisense oligonucleotides
that demonstrate preclinical superiority to the
corresponding stereomixtures.
Within the peptide arena, there has been a
growing recognition that cyclic peptides offer
improved starting points for drug discovery pro-
grams relative to their linear counterparts, largely
due to improvements in entropic cost for binding
and proteolytic stability. Early display platforms
developed to discover cyclic peptides relied on
disulfide formation, and more recently on post-
translational introduction of bis-electrophilesCamposet al.,Science 363 , eaat0805 (2019) 18 January 2019 4of8
Fig. 4. Bio-orthogonal reactivity with proteins at N and C termini.
Fig. 5. High-throughput experimentation to accelerating reaction discovery.
RESEARCH | REVIEW
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