An Old Drug Still Works Great for Monkeypox

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An Old Drug Still Works Great for Monkeypox

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An Old Drug Still Works Great for Monkeypox: Yields Longer-lasting Effects and Reduced Drug Resistance Risk.

Monkeypox, a zoonotic disease, was first identified in monkeys used for research in 1958 and primarily spread among animals.

In 1970, the first human case of monkeypox was documented in the Democratic Republic of the Congo (DRC), and since then, it has been prevalent in several African countries, including Nigeria, DRC, and Central African Republic. Cases of monkeypox outside Africa usually stem from individuals contracting the virus during travel to Africa.

However, during the first half of 2022, monkeypox began spreading in Europe and North America. On July 23, 2022, the Director-General of the World Health Organization (WHO), Tedros Adhanom Ghebreyesus, declared the monkeypox outbreak a “Public Health Emergency of International Concern” (PHEIC).

While smallpox had been eradicated by 1979, the smallpox virus responsible for the disease was still retained in two highly secure laboratories—one in the United States and another in Russia. The threat of bioterrorism using the smallpox virus led to the approval of a drug called Tecovirimat, a broad-spectrum envelope protein inhibitor that showed potent antiviral activity against orthopoxviruses.

In the past year, Tecovirimat has been utilized to treat severe monkeypox cases, but this has also led to the emergence of multiple drug-resistant strains. Therefore, there is a critical need for the development of new treatments for monkeypox.

On August 9, 2023, a team led by Professor Geoffrey Smith from the University of Cambridge and the University of Oxford published a research paper titled “TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6” in the academic journal Nature.

This study unveiled that the cellular protein TRIM5α can inhibit various orthopoxviruses, including monkeypox virus (MPXV), and its action is counteracted by cyclophilin A (CypA) and the viral protein C6.

Crucially, the study further confirmed that existing drugs targeting cyclophilin A (CypA) effectively inhibit the infection and replication of various orthopoxviruses, including monkeypox virus and smallpox virus. These drugs act indirectly on the virus, making it more difficult for the virus to develop resistance.

Professor Geoffrey Smith, the corresponding author of the paper, stated that the identified drugs have longer-lasting effects compared to current monkeypox treatments and are expected to be effective against a range of other orthopoxviruses, including smallpox.

Vaccinia virus (VACV), used to eradicate smallpox, is currently being used for immunization among high-risk populations for monkeypox, such as men who have sex with men.

VACV, cowpox virus (CPXV), monkeypox virus (MPXV), camelpox virus (CMLV), and variola virus (VARV) are all orthopoxviruses that offer cross-immunity protection.

Following the eradication of smallpox, researchers continue to study VACV as a vaccine development platform.

When viruses infect host cells, they must evade host cell proteins that restrict their replication and spread.

This study originated from a simple observation: vaccinia virus (VACV) infection led to reduced levels of TRIM5α in human cells. To understand the mechanism, the research team used CRISPR-Cas9 gene editing to create human cells lacking TRIM5, then overexpressed TRIM5α, TRIM5γ, or TRIM5δ.

The study confirmed that TRIM5α possesses antiviral activity. TRIM5α binds to the capsid protein L3 of orthopoxviruses through its SPRY domain, reducing virus replication and activating innate immunity.

The study also found that several orthopoxviruses, including vaccinia virus, rabbitpox virus, cowpox virus, monkeypox virus, camelpox virus, and smallpox virus, employ two defensive strategies against TRIM5α: the viral protein C6 binds to TRIM5 through its RING domain, inducing proteasome-dependent degradation, and cyclophilin A (CypA) counteracts TRIM5α by interacting with the capsid protein L3, recruiting it to viral factories and particles.

Currently, numerous drugs targeting cyclophilin A (CypA) exist, including CsA, as well as its non-immunosuppressive derivatives Alisporivir and NIM811. Experimental results show that these drugs effectively inhibit the infection and replication of various orthopoxviruses, including monkeypox virus.

CsA is an FDA-approved immunosuppressant used in organ transplants, autoimmune disease treatment, and also has anti-HIV effects.

However, it comes with significant side effects like liver and kidney toxicity. Alisporivir and NIM811 are non-immunosuppressive derivatives of CsA, and both have undergone at least phase 2 clinical trials.

Because these drugs target human cyclophilin A (CypA) rather than the virus itself, the likelihood of developing drug-resistant viruses is lower. These findings provide a basis for testing CsA derivatives against orthopoxviruses, including monkeypox virus and smallpox virus.

Professor Geoffrey Smith expressed astonishment at the unexpected results. The study initially aimed to understand how poxviruses evade host defenses, but it unexpectedly uncovered potential drugs for treating monkeypox and other orthopoxviruses.

Paper link:

An Old Drug Still Works Great for Monkeypox

(source:internet, reference only)

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