lenacapavir to Cure HIV (I)

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Maria Cheng and Gerald Imray, Experts Say a Twice-Yearly Injection That Offers 100% Protection Against HIV Is 'Stunning.' Associated Press, July 11, 2024.Note:

Note:
(1)
(a) The human immunodeficiency virus (HIV)
https://en.wikipedia.org/wiki/HIV
(illustration caption: "Diagram of the HIV virion"/ "It [virus] is composed of two copies of positive-sense single-stranded RNA that codes for the virus' nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24")
is made up of a lipid membrane (called envelope, studded with "env-glycoprotein complex" where env stands for "envelope."

The p in p24 stands for protein, and gp in gp120 (see next) stands for glycoprotein (protein with sugar on top; Ancient Greek adjective masculine γλῠκῠ́ς (romanization: glukús, meaning sweet; noun neuter σάκχαρον (romanization: sákkharon, meaning sugar) ).
(b)
(i) HIV is a retrovirus
https://en.wikipedia.org/wiki/Retrovirus
("that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell")
(ii) Up to 1950s, there was a dogma in biology that genetic material is stored in DNA, Then RNA found in retrovirus (which does not have DNA) turns out to be its genetic material.
(A) en.wikipedia.org for "Rous sarcoma virus" (RSV): "RSV was discovered in 1911 by Peyton Rous, working at Rockefeller University in New York City, by injecting cell free extract of chicken tumour into healthy Plymouth Rock chickens. The extract was found to induce oncogenesis. The tumour was found to be composed of connective tissue (a sarcoma) [as opposed to cancer (which is composed of epithelial or endothelial cells)] * * * In 1958, [] Howard Temin found that RSV's genetic material inside the virus was not DNA] Rous was awarded the Nobel Prize in Physiology or Medicine for the significance of his discovery in 1966")

Rous received a half of the prize that year "for his discovery of tumour-inducing viruses," according to Nobel Prize committee.
(B) RSV's genetic material was found to be RNA. In order to enter and integrate into host DNA, retrovirus needs to transform RNA into DNA, with reverse transcriptase, an enzyme carried within the virus.
https://en.wikipedia.org/wiki/Reverse_transcriptase
("Reverse transcriptases were discovered [actually THEORIZED, because RNA needed to turn into DNA] by Howard Temin at the University of Wisconsin–Madison in Rous sarcoma virions and independently isolated by David Baltimore [with his wife Alice S Huang working in his lab] in 1970 at MIT from two RNA tumour viruses: murine leukemia virus and again Rous sarcoma virus. For their achievements, they shared the 1975 Nobel Prize in Physiology or Medicine (with Renato Dulbecco)" ) (footnotes omitted)


(2)
(a) For decades, gp120 has been the target of HIV prevention or treatment. All attempts on this protein have failed.
(b) The gp120 "was discovered by Professors Tun-Hou Lee and Myron 'Max' Essex of the Harvard School of Public Health in 1984. The 120 in its name comes from its molecular weight of 120 kDa [kilo dalton]. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. * * * [gp120's] Binding to CD4 is mainly electrostatic * * * [The gp20] via non-covalent bonds with the transmembrane glycoprotein, gp41." en.wikipedia.org for "envelope glycoprotein GP120."
(i)
(A) Essex (1939- ) received Doctor of Veterinary Medicine (DVM) from Michigan State University in 1967, and PhD from University of California, Davis in 1970. He was appointed assistant and associate professor with Harvard School of Public Health (1972-1978). See Myron 'Max' Essex. Center for History of Medicine, Harvard Countway Library, undated
https://collections.countway.har ... gmicrobiology/essex
(B) In 1984, Essex was professor and Tun-Hou Lee 李敦厚 was a graduate student (originally from Taiwan, who later became a professor of that school).
(ii) A picture is worth a thousand words. How a HIV virus enters a human lymphoid cell (specifically a T helper cell, whose cellular membrane is characterized by CD4 protein). T stands for thymus 胸腺 because all T cells have to develop in that organ (before being released into the body).

PU Jing et al, Development of Protein- and Peptide-Based HIV Entry Inhibitors Targeting gp120 or gp41. Viruses (published by MDPI), 11: 705 (2019)
https://www.mdpi.com/1999-4915/11/8/705
, whose Figure 1 had coreceptor CCR5 or CXCR4 (standing respectively for "C-C chemokine receptor type 5" and "C-X-C chemokine receptor type 4" whose meaning you need not know). The gp120 (three of them, each with its own CD4 binding site (abbreviated here as CD4bs) and V3 (V stands for variable; each gp120 has five (variable) loops or regions (whose amino-acid sequence are highly mutable among different HIV virus) identified as V1-V5; V3 stands for the third variable loop). Once A gp-120 binds to a CD4 AND, say, CCR5, it (the gp120) is detached, leaving in place gp41 (whose tip is fusion protein (FP), N-terminus is NHR and C-terminus, CHR. The HR in NHR or CHR is explained in the paragraph of text right before Figure 1, but you need not know its meaning.varia

(3)
(a)
(i) lenacapavir
https://en.wikipedia.org/wiki/Lenacapavir
(brand name Sunlenca; "Lenacapavir was approved for medical treatment in the European Union in August 2022, in Canada in November 2022, and in the United States in December 2022. It is the first [so far the only] of a class of drugs called capsid inhibitors * * * Lenacapavir was developed by Gilead Sciences")
, whose name meaning is unclear and whose chemical structure is at the upper right corner of this Wiki page.
(ii) Gilead Sciences
https://en.wikipedia.org/wiki/Gilead_Sciences
(1987- ; full name: Gilead Sciences, Inc; based in Foster City [Foster is the surname of a person], California; section 1 History: company came from Balm of Gilead)
(b) The mechanism of action for lenacapavir is not settled yet, but seems to act on many stages of HIV viral infection.

Pharmacologic Hyperstabilisation of the HIV-1 Capsid Lattice Induces Capsid Failure. eLife, 13:e83605 (Feb 13, 2024)
https://pubmed.ncbi.nlm.nih.gov/38347802/
(At the upper right corner, click "free" to view the full report)

Quote:

(i) Abstract: "The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. * * *

(ii) Introduction: "The cell is a hostile environment for HIV * * * [To achieve the goal for the virus in capsid to] integrate into the preferred sites in the host chromatin [or DNA] The viral capsid [the virus having entered cellular membrane and rid itself of its viral envelope] facilitates these early steps [from viral entry into cellular cytoplasm all the way to entry into nucleus; cell means host cell, as virus is not a cell] in the replication cycle by encapsulating the genome and associated viral enzymes. In doing so, it protects the genome from being sensed and destroyed by nucleases, prevents loss of viral enzymes from the reverse transcription complex, and forms the interface through which all cytoplasmic, and many nuclear, host-virus interactions occur.   The conical capsid shell is comprised of ~1500 copies of the capsid protein (CA), which spontaneously assemble into a lattice. This lattice consists of mostly hexamers and exactly 12 pentamers to form a closed fullerene cone.

"To engage with host cofactors, the mature HIV capsid utilises at least three cytoplasm-facing surfaces. * * * [I will skip the first two routes] The third host-interaction surface, the FG-binding site [to be explained next], is a hydrophobic pocket in the CA [authors' abbreviation for capsid] * * * a phenylalanine-glycine (FG) motif [on capsid; amino acid phenylalanine's one-letter abbreviation is F (from ph) and glycine, G]

View Figure 1(C) where LEN stands for lenacapavir. Further caption of Figure 1 stated, "Landmark residues N57 (pale green) and N74 (red-brown) are highlighted."

"Compounds that target the FG-binding pocket include BI-2, PF74, and lenacapavir (LEN) * * * In contrast to BI-2 and PF74, which have found use exclusively in the laboratory, LEN is a first-in-class HIV-1 capsid inhibitor in clinical trials and approved by the European Union and by the U.S. Food and Drug Administration for clinical use in patients with multidrug-resistant HIV-1 infection. * * * Successive post-entry steps differ in their sensitivity to the drug [LEN], whereby integration of HIV-1 DNA into host chromatin is inhibited most potently (<500 pM), followed by nuclear import and reverse transcription, which is inhibited at high pM [these three steps constituted those three described in the quotation two up]." (citations omitted)


(A) One need not know HIV-1 capsid's 3-D structure to comprehend lenacapavir. But I will indulge you.
• fullerene
https://en.wikipedia.org/wiki/Fullerene
("consist of carbon atoms connected by single and double bonds so as to form a closed or partially closed mesh, with fused rings of five to six atoms. The molecules may have hollow sphere- and ellipsoid-like forms, tubes, or other shapes. * * * The family is named after buckminsterfullerene (C60 [made up of sixty carbon atoms]), the most famous member, which in turn is named after Buckminster Fuller")
• p24 capsid protein
https://en.wikipedia.org/wiki/P24_capsid_protein
(top figure)
• The en.wikipedia.org has a page titled "HIV capsid inhibition" which is not informative.
(B) "HIV-1 capsid protein is a 231-amino-acid protein": from the Web. One-letter abbreviation N stands for amino acid asparagine. The amino acids HIV in capsid at positions 57 and 74 are both asparagine, and yet this article did not explain why these two amino acids were critical.