What is This Medication
INTRODUCTION
A NON-TOXIC Medication
Antiviral Composition, U.S. Patent November 23, 2004: 6,821,958 is identified as
NIAID Compound # 11039 and is a solid, stable, non-toxic white powder at room
temperature showing anti-HIV activity in the parts per million concentration
range. The compound of the invention provides antiviral activity, particularly
in the treatment and prevention of sexually-transmitted diseases including HIV
and Herpes. Methods of treating or preventing HIV viral infection include
administration orally and/or topically.
The active compound comprising an alkylsulfate derivative of a sulfated dextrin
starting material having a molecular weight of at least 3,000, wherein the
sulfated dextrin starting material is sulfonated to form the alklysulfate
derivative of sulfated dextrin, wherein the range of sulfonation of the
alkylsulfate derivative of sulfated dextrin is between 12 to 21%, wherein the
sulfonation occurs in clusters of alkylsulfate groups and sulfate groups present
on the branch point structures of the sulfated dextrin, and further wherein the
ratio of alkylsulfate groups to sulfate groups is about 1 to 2.
Compound #11039 is the first polymethysulfonated polysulfonated microbicide or
oral compound for the prevention or treatment of HIV infection. Compound #11039
is believed to inhibit the binding to either variable or conserved binding sites
of the HIV particle or cellular receptors, thus preventing infection. The
mechanism of action is discussed below, however the exact mechanism of action
will require further study.
The representation of the active binding structure is represented by the
structure presently below. Three sulfate groups form a ridge of negative charge
to bind to the positive protein pocket. The ability of the sulfate group to
provide many binding options is eventually captured at an optimum biding energy
as the methylsulfonate group anchors the molecule. Theoretical removal of
intermolecular water in the area of the methylsulfate carbohydrate binding or
hydrogen binding arena would increase the binding affinity. This effect is shown
in experiments where the excess drug is removed from the cellular surface by
washing prior to viral challenge.
On the structure below the ridge of sulfate binding can be easily seen.
The red colored sulfate ions spread out nicely on one geometric side as a fan
on two different glucose molecules from the 1-6-branch point link. The
substitution of the hydroxyls on C-2, C-4 and C-6 positions are represented. The
key structural component for inhibitorial binding could be result of two closely
spaced sulfonates, but one is sufficient for the explanation of the drugs
mechanism of sction.
The second binding site is represented on the structure by two methysulfonate
groups on C-4 and C-6 of the second branch point glucose molecule form the 1-4
link. A sweeping non-hydrogen binding void can be filled by the structure. Below
the linear space filling structure demonstrates the proposed binding interaction
volume.
The data from specific cellular test conducted independently at the Southern
Research Institute thru contract with the NIAID, the REGA Institute and St.
Georges Hospital of the U.K. show in vitro anti-HIV activity in the ppm (parts
per million). The most complete data is represented by the NIAID contracted data
from the Southern Research Institute presented below.
From the data the most active binding occurs with the assays of the R5-Tropic
Attachment assays and the X-4Tropic Attachment assays. This represents the
maximum binding affinity in challenge to the virus at the concentration of about
one part per million and only falls by about a factor of ten when the challenge
is an infected cell as represented by the R5-Tropic cell to cell and the
X4-Tropic cell to cell assays. This demonstrates that the viral proteins exposed
on the surface of an infected cell are readily accessible despite the complex
surface nature of a human cell as compared to that of an isolated viral
particle. It also demonstrates that is a common pathway between a lone viral
particle challenge and an infected blood cell challenge.
This common mechanism would predict that bodily fluid containing active compound
NIAID #11039 of the structure type described above would be both preventative of
HIV infection and be use for treatment of HIV infection. Therefore, providing
the compound externally is one method and would be used to describe the compound
as a microbicide. Oral ingestion of the compound would result in digestion by
amylase type action on the larger molecules of the compound allowing structures
represented by the above structure to pass into the blood stream. Extravagation
of the compound with white blood cells into the vaginal mucosal fluids along
with the common CD4 cell provides an secondary mechanism to provide possible
protection during intercourse. Similarily, one would expect semen in the mail to
potentially behave in the same fashion and actually carry deactivating or
anti-HIV compound.
Three dimensional optimization of the flat structure in stick form is shown
below.
This first step in QSAR analysis demonstrates an interesting possibility that the active site prevents protein movement required to form a channel or tunnel for the viral particle RNA to enter the human host. Crowding of the hydroxyl groups of the adjacent branch point glucose molecules is more evident on the space filling structure below.
The binding domain now can be demonstrated by the structural stability and
rigidity of the branch point structure of the alpha 1-4 and alpha 1-6 link
carbohydrate links in the face of two opposed binding moieties.
A simple sulfonate or simple sulfate, as termed here, such as Cellulose Sulfate
required a 6% solution for the desired anti-HIV effect. This concentration of
six percent of Cellulose sulfate is however caustic to the vaginal wall and
resulted in the increase in spread of HIV compared to placebo during large
multinational FDA phase III clinical trials. Despite the presence of an
important anti-HIV activity the World Health Organization stopped the clinical
trials because of the obvious detriment.
No simple sulfates or sulfanates can provide enough specific binding site anchor
despite maximizing the binding energies by changes in the total molecular weight
of the compound and the percent sulfonation. The early theories considered that
the sulfate groups were to bridge two binding sites. The theory placed much
weight on the sulfate negative charges, their separation distance and resulting
binding over a rather large area of the CD4 cell surface. Essentially only
providing one biding site per CD4 receptor complex-viral gp120/41 protein
complex. To provide enough binding energy a relatively large structure is
required because of the active dynamics of attachment - detachment equilibrium
rates occurring causes dislodgement of any particular binding event in
discussion.
The early theory ignored the possibility of the presence of a second binding
site within a smaller area. Fewer sulfate groups would be required to achieve
sufficient binding energy because of the presence of the second binding site. In
addition, the combination of the formed sulfonate – protein binding interaction
along with a methylsulfonyl - protein binding interaction defines a molecular
mechanism of action defined within the realm of one CD4 receptor complex-viral
gp120/41 protein complex. Simple sulfates can not achieve this form of
inhibition.
The addition of the mesyl type methylated sulfonate group provides a second
biding site helping to stabilize the sulfonate binding. The unique combination
of binding inhibits the interaction of the relatively stable gp120 and gp41
proteins of the HIV envelop and the stable CD4 CCR5 and X4 proteins of the CD4
receptor system. This mechanism does both of inhibiting viral entry into the CD4
white blood cell and inhibiting transfer of virus from an infected cell into a
non-infected cell, a process termed syncitial formation. The compound therefore
presents an excellent candidate for the prevention and treatment of HIV
infection.
CHEMISTRY, MANUFACTURING AND CONTROLS
Compound #11039 is a new chemical entity resulting from the reaction of
sulfonating and methylsulfonating reagents on corn starch. The starting
material, dextrin, is a food product. The current established protocol for the
manufacture and controls of Compound # 11039 presently proprietary information.
PHARMACOLOGY / TOXICOLOGY
Compound # 11039 is a solid non-toxic white powder at room temperature. An
initial oral study in rodents has demonstrated Compound #11039 to be non-toxic.
Chemistry design software provided by Advanced Chemistry Development
Medical information: Cure HIV, Inc. does not intend to provide specific medical advice or treatment. Cure HIV, Inc. intends to provide the website visitors with documents and information to better understand HIV / AIDS and its prevention and treatment.