Comparative Computational study

on Nipah virus Drugs.

Introduction
In the present era of emerging technology, the act of war between the countries will
lead to the complete destruction of the earth because the nuclear weapons which
have been developed by the countries for their safety will not only demolish one
nation but whole of the world in some or the other way. Therefore, any country will
not take the risk of using nuclear weapons to destroy their enemy nation. However in
order to take revenge now the countries are using biological agents to destroy their
competitor country. This act is known as bioterrorism. Bioterrorism attack can be
defined as the purposeful release of viruses, bacteria or other biological agents
which causes ultimate death and are further transmitted to other organisms. main
reason of spreading bioterrorism attack is to affect the productivity of the country
which will lead to economic breakdown. The major pathogens which are used as

biological weapon are anthrax, plague, equine encephalitis virus etc. Recently few
years back one new brain damaging virus was discovered which although was a
natural phenomenon emergence but many scientists considered it as a biological
weapon named as Nipah Virus( NiV).
 NiV was first discovered in Malaysia in 1999 and was named after the place of
discovery which was Sungai Nipah, Malaysia.

Nipah virus

Nipah (Nee-pa) viral disease is a zoonotic infection and an emerging disease

caused by Nipah virus (NiV).It is an RNA virus of the genus Henipavirus, family
Paramyxoviridae, which is transmitted by specific types of fruit bats, mainly Pteropus
spp. NiV is a highly fatal virus posing potential threat to global health security.

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 NiV is transmitted zoonotically (from bats to humans, or from bats to pigs, and
then to humans) as well as human-to-human routes. Its clinical presentation varies
from asymptomatic (subclinical) infection to acute respiratory illnesses and fatal
encephalitis in most of the patients who has been in direct contact with infected pigs.
It has also been found that the virus causes central nervous system illnesses in pigs
and respiratory illnesses in horses resulting in a significant economic loss for
farmers. Large fruit bats of the genus Pteropus seem to act as a natural reservoir of
NiV based on the isolation of Hendra virus which has showed the presence of
neutralizing antibodies to the Hendra virus on the bats.

Geographic distribution:-

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Nipah virus has been isolated from Lyle’s flying fox (Pteropus lylei) in Cambodia and
viral RNA found in urine and saliva from P. lylei and Horsfield’s roundleaf bat
(Hipposideros larvatus) in [Link] virus has also been isolated from
environmental samples of bat urine and partially eaten fruit in Malaysia. Antibodies
to henipaviruses have also been found in fruit bats in Madagascar (Pteropus rufus,
Eidolon dupreanum)and Ghana (Eidolon helvum) indicating a wide geographic
distribution of the viruses. No infection of humans or other species have been
observed in Cambodia, Thailand or Africa as of May 2018 .

Structure:-

Nipah virus is an enveloped virus, pleomorphic in shape (40 ‐1900 nm) having
single‐stranded negative‐sense RNA genome. Under electron microscope, NiV has
similar morphological structure pattern as that of other members of Paramyxoviridae.
NiV is placed along with HeV in the genus Henipavirus of family Paramyxoviridae as
NiV showed 68% to 92% and 40% to 67% homology with HeV in protein ‐coded
regions and non‐translated regions, respectively. Like other Paramyxoviruses, NiV
also has six genes which encode for fusion protein (F), glycoprotein (G), matrix

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protein (M), nucleocapsid (N), phosphoprotein (P), and polymerase protein (L).
Phosphoprotein (P) gene encodes various important accessory proteins known as C,
V, and [Link] C protein plays a very important role in regulation of viral RNA
synthesis and virulence factor. V and W proteins are crucial for virulence, and these
proteins act by inhibiting the activation of an interferon ‐inducible promoter. Strain
variations have been observed between human NiV isolates collected from the
outbreaks in Malaysia, India, and Bangladesh. Similarly, NiV virus isolates from bats
samples which were collected from different geographical area also displayed
genomic variation. NiV is a newly emerging virus, and also high containment facility
is required for NiV study; therefore, limited data is available on virus replication,
transcription, translation, and other mechanisms.

Clinical and Epidemiologic Features of Nipah Virus in Humans :-

Nipah virus causes severe acute febrile encephalitis with virus infiltrating most
major organs and endothelial cells. Laboratory tests used to make a definitive
diagnosis include viral isolation, immunohistochemistry (IHC), polymerase chain
reaction (PCR), and serology. In fatal cases of acute Nipah virus encephalitis, there
was an 81% correlation between serology and IHC. Retrospective diagnosis of
Nipah virus used a case definition that included contact with pigs or other infected
animals and inhabiting a known outbreak site.

Nipah virus outbreak in Malaysia:-

Nipah virus emerged in Malaysia in 1998 to 1999 as a porcine respiratory and

neurologic disease and was transmitted to humans. The outbreak of encephalitic
disease in pigs spread through peninsular Malaysia as infected animals were
shipped between farms from north yo south and into Singapore. There were a total
of 265 human cases of Nipah virus infection in Malaysia and a further 11 in
Singapore [16]. Of those infected, nearly 40% (105) died. Almost all cases were
directly associated with the pig industry, suggesting that Nipah virus in Malaysia is
either unable or unlikely to spill-over from its reservoir directly to humans.

The predominant symptoms in Malaysian patients were fever, headache, altered

mental state, vomiting, and Loss of consciousness, Myoclonus, areflexia, and

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tachycardia were among the signs that indicated brain stem dysfunction and central
nervous system (CNS) involvement. Less than 20% of patients presented with
coughing or other upper respiratory signs, despite the presence of virus in the upper
respiratory tract. Coughing was a more prominent feature (40%) in cases of fatal
acute Nipah virus encephalitis. The relatively low occurrence of coughing may
explain the lack of human to human transmission in the Malaysia outbreak. Relapse
of Nipah virus encephalitis occurred in 12 acute encephalitis survivors (7.5%) and
delayed onset (average 8.4 months) occurred in 10 cases (3.4%). Of these late-
onset and relapse cases, four died and the rest had persistent neurologic deficits. In
cases of acute fatal Nipah virus encephalitis, the virus was identified in the CNS,
lungs, kidneys, spleen, Lymph nodes, and endothelial tissue of the smaller blood
Vessels. Typical lesions included widespread vasculitis, particularly in the CNS,
heart, lung, and kidney, with multinucleated giant endothelial cells sometimes
present In these organs. Viral inclusion bodies were present in the cytoplasm and
nuclei of neuronal cells. Viral antigen was Seen by IHC staining in the blood vessels
of most organs, particularly where vasculitis was present. Many of the pathologic
findings of acute fatal Nipah virus encephalitis are common to other encephalitic
diseases; however, the presence of syncitial multinucleated endothelial cells is
characteristic of Nipah and Hendra virus infection.

Nipah virus outbreak in Bangladesh:-

Five outbreaks of human Nipah virus infection have been recognized in Bangladesh
between 2001 and 2005. To date, 102 human cases of Nipah infection have been
documented in Bangladesh; 76 (75%) of these were [Link] data
suggest four major differences between the outbreaks in Bangladesh and those in
Malaysia and singapore: 1) Nipah virus has spilled over into the human population
repeatedly in five independent outbreaks;2) spillover appears to be seasonal; 3)
spillover occurred without livestock amplifier hosts; and 4) there is strong evidence of
human-to-human transmission. Genetic characterization of the Nipah virus isolated
from humans in Bangladesh in 2004 showed it to be distinct from the Malaysian
strain, with the two viruses having approximately 92% nucleotide sequence
[Link] patients presented with fever and central nervous system symptoms,
and a severe respiratory illness was reported in some.

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Laboratory diagnosis:-

Laboratory diagnosis of Nipah virus infection is made using reverse transcriptase

polymerase chain reaction (RT-PCR) from throat swabs, cerebrospinal fluid, urine,
and blood analysis during acute and convalescent stages of the disease. IgG and
IgM antibody detection can be done after recovery to confirm Nipah virus infection.
Immunohistochemistry on tissues collected during an autopsy can also confirm the
disease. Currently, there are no effective treatments for the Nipah virus infection.
Therefore, a few precautions should be followed such as practicing standard
infection control, barrier nursing to avoid the spread of the infection from person to
person, and the isolation of those suspected to have the infection. Recent
computational approaches have provided further information about viruses, including
the study conducted by Badawi M et al. On Zika virus, where the envelope
glycoprotein was obtained using protein databases. The most immunogenic epitope
for the T and B cells involved in cell-mediated immunity was previously analyzed.
The main focus of the analysis was the MHC class I potential peptides using in silico
analysis techniques.

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Treatment of Nipah virus Infection:-

There are currently no vaccines or antivirals approved for combating human NiV
infections.

1)Favipiravir

Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against
emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in
the United States and Europe. Favipiravir has demonstrated efficacy against a broad
spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae,
Arenaviridae families, and the Bunyavirales order. We now demonstrate that
favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir
inhibited Nipah and Hendra virus replication and transcription at micromolar
concentrations. In the Syrian hamster model, either twice daily oral or once daily
subcutaneous administration of favipiravir for 14 days fully protected animals
challenged with a lethal dose of Nipah virus. This first successful treatment of
henipavirus infection in vivo with a small molecule drug suggests that favipiravir
should be further evaluated as an antiviral treatment option for henipavirus infections

2) Ribavirin

As per NIV study, Ribavirin helps reduce viremia in patients infected with Nipah virus
but there has been no proof yet that it is an effective treatment for Nipah virus
[Link] doctors in Malaysia who have administered Ribavirin in Nipah-infected
patients have also confirmed its promising effects in slowing the virus from spreading
all over the body. For best results, the doctors advise that the treatment should be
given within 2-3 days after an individual shows symptoms of Nipah infection.

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3)Remdesivir

Lo et al. tested the nucleotide prodrug remdesivir (GS-5734), which has shown
activity against other pathogens such as Ebola virus, in a nonhuman primate model.
Animals were administered a lethal dose of Nipah virus, and half were treated daily
with remdesivir starting 24 hours later. All control animals had to be euthanized, and
although treated animals had some mild symptoms, all survived. These results
indicate that efficacy of remdesivir should be tested in human Nipah virus infection.