Origene_Jan2021_ProperAntibodyDesignKeeps - 16

Nanobody Approach Prevents the Culling of Imperfect but Still-Functional Proteins
normalized action potential duration. CF-targeted

One of the targets was a protein mutated in CF. The

enDUBs synergistically rescued common and

other was a protein mutated in LQT syndrome, an

pharmacotherapy-resistant CF mutations when

inherited heart disease that can cause arrhythmia

combined with [drugs that have already been

and sudden death.

approved by the FDA]. "

" Altogether, " the authors of the Nature Medicine
article asserted, " targeted deubiquitination via

In the case of one of the

enDUBs provides a powerful protein stabilization

cystic fibrosis proteins we

method that not only corrects diverse diseases

tested, we get a remarkable
rescue, restoring protein
levels in the cell membrane
to about 50% of normal. If

caused by impaired ion channel trafficking, but
also introduces a new tool for deconstructing the
ubiquitin code in situ. "
The Columbia team, which was led by Henry
Colecraft, PhD, also noted that deploying enDUBs
should be more effective than simply increasing

that happened in a patient, it

DUB activity and indiscriminately rescuing

would be transformative. "

all proteins in a cell marked for destruction.

		 Henry Colecraft, PhD,
Columbia University

Suspending all protein destruction in the cell would
be harmful.
Colecraft observed that in many genetic

The enDUBs are modified deubiquitinases. Like

diseases, including cystic fibrosis, mutated proteins

ordinary deubiquitinases, the enDUBs remove the

are capable of performing their jobs but are

ubiquitin tags-small peptides that say " destroy

tagged for destruction by the cell's quality control

me " -that are applied by the ubiquitination system.

mechanisms. " The situation is analogous to ugly

The enDUBs, however, incorporate a synthetic

fruit, " he said. " Shoppers reject fruit that doesn't

nanobody that recognizes a specific protein.

look perfect, even though ugly fruit is just as

Natural nanobodies are small antibodies

nutritious. If mutated proteins in cystic fibrosis can

produced by llamas, camels, and alpacas. These

escape the cell's quality control mechanisms, they

molecules, which were discovered nearly 30 years

work pretty well. "

ago, bind their targets with exquisite specificity

" A lot of proteins are destroyed by the cell for

and retain this property inside cells, unlike

good reason, " Colecraft added, " so a therapy needs

regular antibodies.

to be selective. "

In the current study, nanobodies were produced
that recognized and bound only selected targets.

16 |

GENengnews.com

To build each enDUB, Colecraft and colleagues,
including graduate student, Scott Kanner, first
http://www.GENengnews.com
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