Assay and Drug Development Technologies - 3

Recently, 10x Genomics launched Chromium X, a nextgeneration
singlecell platform that can be used with the company's
new high-throughput assays to enable cost-effective,
large-scale, single-cell experiments. The company offers many
other technologies, including Visium, a spatial gene expression
technology.
FUNCTIONALLY FLEXIBLE GPCR DRUGS
GPCRs constitute the largest and most diverse set of
membrane proteins in the body. Members of this receptor
super-family bind to a broad range of molecules and help
direct many key physiological processes. ''Because GPCRs are
involved in various diseases, they account for about one-third
of all market drugs,'' says Christel Menet, PhD, CSO Confo
Therapeutics. ''But they still face many challenges such as
lack of specificity and unwanted side effects.''
Menet advises that while therapeutic antibodies and other biologics
have gained considerable attention with the launch ofthe
first two GPCR-targeting antibodies (erenumab and mogamulizumab),
the discovery of such antibodies remains challenging.
''As far as we are aware, all GPCR antibodies that are in
development or on the market are antagonists,'' she continues.
''Confo has demonstrated that, in addition to structure-based
drug discovery of small molecules, its unique technology to
stabilize the GPCR in its native conformation and natural
environment can also be leveraged to discover agonistic biologics
with very high potency and selectivity.''
To stabilize GPCRs, the company uses ConfoBodies, singledomain
antibodies specific for a particular target conformation.
They are generated by state-ofthe-art VHH (single domain antibody
fragment) discovery methods, either from immune or nonimmune
libraries. Menet elaborates, ''We also recently discovered
more universal methods to applying the Confo technology
without theneed foranadditionalConfoBodydiscoveryforevery
new GPCR target we want to drug. This of course drastically
improves the efficiency and success rate of our approach.''
Once Confo scientists are happy with the pharmacological
profile of the Confo-Body, they use the ConfoBody-stabilized
GPCR as the driver for their drug discovery process for chemical
and/or biologics approaches. ''The resulting therapeutic
candidates,'' Menet explains, ''are then characterized in a
cascade of different in vitro and in vivo models to examine
their relevance for treating the disease(s) of interest.''
The company is building its proprietary pipeline and expanding
its outlook. ''We would like to be able to pursue any
therapeutically relevant GPCR, including less-wellcharacterized
and orphan GPCRs,'' Menet comments. ''Ideally,
we would also expand beyond GPCRs to other classes of
membrane proteins.''
DIGITAL INFO IN, MRNA OUT
Vaccine and therapeutic researchers are increasingly focusing
on mRNA-based platforms for discovery, especially in
light of the success of the mRNA-based COVID-19 vaccines.
''Typically, mRNA discovery workflows begin with an iterative
design-build-test process that requires researchers to
design their candidate mRNA molecules and synthesize them
prior to testing or screening for promising lead molecules,''
observes Jyotsna Venugopal, PhD, director of product marketing
at Codex DNA. ''This process can be confoundingly
empirical. It can take multiple iterative cycles before lead
molecules are identified.''
To address this challenge, Codex DNA has developed a
novel mRNA solution. ''Our automated benchtop synthetic
biology workstation-the BioXp 3250 system-enables handsfree
synthesis ofmRNA in a single overnight run,'' Venugopal
asserts. ''This empowers researchers to avoid the weeks or
months of wait time and challenges associated with acquiring
synthetic mRNA and thus accelerates the evaluation of candidate
molecules in their discovery process.''
The instrumentation performs all the steps required to go
from DNA oligos to synthesized, assay-ready mRNA in a
single automated run. According to Venugopal, accomplishing
all these steps in a typical laboratory can require multiple
scientists, numerous steps, varied skill sets, and long lead
times. ''In contrast,'' she says, ''the BioXp 3250 can produce up
to 16 synthetic mRNAs in a single automated, overnight run.''
Venugopal also notes the importance ofcooperative efforts:
''We have collaboration agreements with various industry
partners and believe this is important to advancing our mRNA
workflow solutions for key applications.''
PROTACS AND TUBES
A promising drug discovery approach is targeted protein
degradation. To date, this approach has emphasized the development
of small-molecule drugs called PROteolytic TArgeting
Chimeras (PROTACs). These ''degrader'' drugs work by
targeting the ubiquitin-proteosome system (UPS).
PROTACs are heterobifunctional molecules that consist ofa
ubiquitinligase-targeting ligand, a chemical linker, and a
distinct protein-binding ligand. The complex promotes protein
degradation via production of polyubiquitin chains on
the protein of interest.
''The major problem in PROTAC drug discovery is slow
PROTAC design, synthesis, and testing,'' observes Karteek Kadimisetty,
PhD, director of R&D at LifeSensors. ''The PROTAC
community needs a fast method for monitoring PROTAC
function and generating reliable data. LifeSensors has translated
the traditional western blot assay into a faster method by
ª 2022 GEN PUBLISHING Genetic Engineering & Biotechnology News 3
Assay and Drug Development Technologies

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