How do humans reach the microscopic world?

- A strategy for the early stages of drug development using Covid-

19 as an example

In December 2019, a number of cases of

unexplained pneumonia emerged in several hospitals Diffraction:
A physical phenomenon in
in Wuhan, China, which were eventually confirmed to
which a wave deviates
be acute respiratory infections caused by the novel
from its original straight-
coronavirus. This outbreak eventually became a line propagation when it
worldwide pandemic, and to this day, the impact of encounters an obstacle,
this pandemic on our lives has still not completely such as a slit, a small hole,
dissipated. As we take off our masks and get back on or a disk.
track with our studies and work, do we ever wonder
how this pandemic, which is so relevant to all of us,
has influenced our medical care? And how were those
miraculous antiviral drugs created?

Diffraction. Isaacphysics.org
Structure: What does the molecule look like?
The determination of the structure is an essential
part of the search for an applicable drug against a
particular virus. Like a puzzle, we need to use the N/C-terminus:
surrounding puzzle to determine the location of an The primary structure of a
unknown piece. Currently, the most widely used protein consists of a
techniques in the field of biomolecular structure peptide chain composed of
determination are based on diffraction, such as X-ray amino acids, and the N/C-
crystallography. Ya Peng's team, one of the most terminus are the start and
advanced Chinese teams studying SARS-CoV-2, has end point of the peptide
performed data collection and modeling of the chain respectively; the N-
crystallized SARS-CoV-2 virus using diffraction terminus has a free amine
group (-NH2) and the C-
techniques. The structures revealed that both the N-
terminus has a free
terminal domain (N-NTD) and the C-terminal domain
carboxyl group (-COOH).
(N-CTD) of the nucleocapsid protein (N protein) of
SARS-CoV-2 virus show conserved features with other
coronaviruses, such as SARS-CoV. The presence of
such conserved features is of great promise for the
development of targeted drugs.

Illustrated Glossary of Organic

Breakthrough: What do N proteins mean? Chemistry. chem.ucla.edu
The viral nucleocapsid protein, often referred to
simply as the N protein, is one of several important
proteins possessed by viruses. It is unique in that it has
the ability to bind to viral RNA. We know that DNA
represents the genetic information of all living things.
When a virus invades a host cell, it embeds the
RNA it carries into the cell's genetic information and
uses the host cell's ability to replicate the genetic Nucleocapsid protein:
information to convert the viral RNA into DNA, which
is eventually "transmitted" to other cells. This process
is known as reverse transcription. The nucleocapsid
protein is closely related to this process, as its ability to
tightly bind to the viral RNA can protect the RNA
from being destroyed by the body's immune system;
and after the virus enters the host cell, it can separate
from the RNA as soon as possible to achieve maximum
efficiency.
Nucleocapsid expression.
Does this give us an insight? Invivogen.com
Of course! Since the binding between the
nucleocapsid protein and the RNA ensures the
successful reverse transcription process, disrupting
Reverse Transcription:
this binding can achieve the purpose of viral
Reverse transcription is the
suppression! If you have a similar idea, then
process of synthesizing
congratulations you already have a talent for drug
DNA using RNA as a
design. Since the RNA-binding activity of the N template. It is opposite to
protein is essential for the formation of nuclear the direction of normal
genome replication of the viral ribonucleoprotein genetic information flow
(RNP), then blocking the binding of N-NTD to RNA in (DNA to RNA).
the N protein, or blocking the normal N protein
oligomerization could be good strategies for
developing antiviral drugs. This process of exploring
the mechanisms by which a drug will work against a
disease is often called target validation, which is the
first step in drug research. Reverse Transcriptase & cDNA
Overview & Applications.
Goldbio.com

Peng, Ya et al. “Structures of the SARS‐CoV‐2 Nucleocapsid and Their

Perspectives for Drug Design.”
Expansion: What can we do after finding a
target?
Although Ya Peng's article ends with the
conclusion that N protein may be able to be a target for
antiviral drug design, it leaves us with a big thought:
what can we do after finding a target?
General drug development is usually divided into
three phases:
The first is the preclinical research phase. After Pharmacodynamic:
A main branch of
confirming the fact that the N protein is a potential
pharmacology, which is the
target, by using 3D modeling of the N-terminal
study of how a drug affects
domain of the N protein, we can apply molecular an organism.
visualization software to find the active site of the
protein, and design small molecules that bind to it by
examining the properties of the amino acid residues
near the binding site. These potential drugs are then Toxicology Test:
screened and conducted by pharmacodynamic studies Also called safety
and toxicology tests. These studies usually take place assessment. It is the process
in animals. of determining the degree
The second is the clinical phase. Researchers will to which a substance
recruit volunteers for drug testing. The clinical phase is negatively impacts the
divided into three phases, each with a different normal biological functions
purpose. of an organism.
The third is the manufacturing and post-marketing
studies. After clinical testing is passed, the drug will be
approved for marketing. This phase of the study is
designed to examine the efficacy and side effects of the
drug on a large scale.

Expansion: How is the research progressing

so far?
In addition to the N protein, existing studies give
more effective targets for SARS-CoV-2 virus, such as
Spike Protein, Envelope Protein, and Membrane
Protein. Based on the N protein as a drug target,
another Chinese research team designed 16 molecules
as phenanthridine inhibitors, two of them were
validated to be effective against SARS-CoV-2 virus.
There are many promising results like this, and more
and more drugs are entering the clinic phase, and I
believe they will soon be available to the public.
Conclusion: How do humans reach the
microscopic world?
In the early stages of antiviral drug design,
obtaining the 3D structure of the target virus and
perform a target validation are critical. Since the N
protein plays a key role in viral replication, designing a
drug that inhibits the action of the N protein may be a
breakthrough in drug design. After designing
theoretical small molecule drugs, we need to go
through three phases to make it a mature and safe
product: preclinical research phase, clinical phase, and
manufacturing and post-marketing studies.

Curiosity: Want to know more?

If you still want to be deeper, here are some
recommended Web pages that cover some of the
concepts mentioned in this article. Hope these will
help you!

1. Original Article: Structures of the SARS‐CoV‐2

nucleocapsid and their perspectives for drug design
| The EMBO Journal (embopress.org)
2. Another advanced research: Novel nucleocapsid
protein-targeting phenanthridine inhibitors of
SARS-CoV-2 - PubMed (nih.gov)
3. X-ray Crystallography: X-ray crystallography -
Wikipedia
4. Nucleocapsid Proteins: Virus - Wikipedia
5. Reverse Transcription: Reverse transcriptase -
Wikipedia
6. Amino acids: Amino acid - Wikipedia
7. Target Validation: Target Validation in Drug
Discovery | Sygnature Discovery
8. Different stages of drug development: Drug
development - Wikipedia